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PubMed2026

Estimation of chloroplast macromolecular complex copy numbers and subunit stoichiometries during the Chlamydomonas reinhardtii cell cycle.

An unbiased, quantitative view of biomolecules in a living cell is a prerequisite for accurate modeling approaches and informs our understanding of cellular metabolism at scale. In this work, we used the total protein approach (TPA), in which the total protein mass of a given proteomics sample is used as a calibrator for absolute protein quantification, to determine protein abundances during the Chlamydomonas reinhardtii diurnal cycle. We use external, independently measured quantitative markers (metals, pigments) to assess the absolute protein abundances in unlabeled whole cell extracts. We calculate protein abundances in fg cell-1 of 7322 Chlamydomonas proteins, 2266 of which were captured in every time point, including the major proteins involved in the light reactions, photoprotection, proteostasis, and fatty acid metabolism during a cell cycle. As expected, Rubisco large and small subunits are present in a 1:1 stoichiometry, with the large subunit being the most abundant protein in our data set, averaging 5.05 × 106 molecules per cell, reflecting 2.7% of the total protein mass. We noticed that PSII is the most abundant complex involved in the light reactions with 2.08 × 106 complexes per cell. PSI averages 1.75 × 106 complexes per cell and cytochrome b6f averages 0.77 × 106 complexes per cell. The TPA is a robust tool to study proteome dynamics quantitatively, while avoiding artifacts due to biochemical fractionation. Our proteome data set with an unprecedented temporal resolution is a valuable resource to assess protein abundances during the cell cycle in the reference alga Chlamydomonas.

Chlamydomonas reinhardtii↗
PubMed2025

COG6 is an essential host factor for influenza A virus infection.

Influenza A virus (IAV) relies on the host cellular machinery to support its replication. Understanding these host dependencies can inform the development of novel antiviral strategies. In this study, we identified conserved oligomeric Golgi complex subunit 6 (COG6) as a novel host factor critical for IAV replication through a genome-wide clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) knockout screen. Disruption of COG6 significantly impaired viral replication. Mechanistically, COG6 supports IAV replication via two distinct means. First, consistent with the role of the COG complex in Golgi homeostasis, COG6 is required for the proper presentation of surface sialic acids, the primary receptor for IAV entry. Second, COG6 deficiency unexpectedly led to lysosome-dependent degradation of viral proteins. Notably, lysosomal activity was also upregulated in IAV-infected wild-type cells, albeit to a lesser extent than in COG6-deficient cells. Treatment with lysosomal inhibitors rescued viral protein stability in COG6 knockout cells. Protein interaction analysis further demonstrated that COG6-mediated stabilization of viral proteins did not rely on viral protein-COG6 interaction, refuting the hypothesis that COG6 acts as a shield factor to protect viral protein from lysosomal degradation. Moreover, knockout of other COG subunits produced similar antiviral effects, suggesting that an intact COG complex is required for IAV replication. Together, these findings uncover a critical role of the COG complex in regulating IAV replication and highlight a previously unappreciated functional link between the Golgi and lysosomes that could be exploited for treating IAV infections.IMPORTANCEDespite advances in virology, numerous host determinants facilitating influenza A virus (IAV) pathogenesis remain uncharacterized. Our study establishes conserved oligomeric Golgi complex subunit 6 (COG6) as a critical host factor promoting IAV infection through complementary mechanisms: receptor modulation and viral protein stabilization. This represents the first demonstration that the COG complex regulates viral pathogenesis through proteostasis mechanisms, fundamentally expanding our understanding of host-virus interactions at the organelle interface. These findings not only provide new perspectives on viral exploitation of Golgi trafficking networks but also identify potential therapeutic targets against evolving influenza strains.

Influenza A virus↗
PubMed2026

Comparative Transcriptomics Reveals Shared Downstream Pathways in Craniofacial Pathology.

Treacher Collins syndrome and Nager syndrome are craniofacial developmental disorders caused by defects in ribosome biogenesis and RNA splicing, respectively, yet they exhibit overlapping abnormalities affecting neural crest cell-derived craniofacial structures. To investigate shared downstream pathogenic mechanisms, we performed a comparative transcriptomic analysis of zebrafish polr1c and sf3b4 mutant models from our previous studies. Comparative analysis identified 17 shared differentially expressed genes (DEGs) between polr1c and sf3b4 mutants, with the majority of shared genes dysregulated in the same direction, indicating a coordinated rather than random transcriptional response. Gene ontology analysis identified ATP-dependent protein folding chaperone activity as the only shared molecular function, driven in part by upregulation of hsp90aa1.2, indicating a common proteostasis response. Because chaperone activity is linked to extracellular matrix (ECM) protein processing, we cross-referenced DEGs from both mutants against the curated zebrafish matrisome. Three of the 17 shared DEGs (serpinh1b, il11a, and lepa) were matrisome-associated and upregulated in both mutants. Serpinh1b, a collagen-specific chaperone, was strongly expressed in craniofacial cartilage and mesenchymal populations during pharyngeal arch development and exhibited nearly identical fold changes in both mutants. Il11a is of particular interest because its receptor, IL11RA, is known to be associated with human craniosynostosis, suggesting potential relevance to craniofacial development. Together, it is possible to hypothesize that shared chaperone-associated transcriptional changes, together with altered ECM-related gene expression, may contribute to polr1c- and sf3b4-associated craniofacial disorders, warranting further functional validation.

Extracellular Matrix↗
PubMed2026

Hepatic metabolic adaptation to endurance exercise: temporal and sex differences by multiomics integration and validation.

BACKGROUND: Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. METHODS: Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. RESULTS: The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. CONCLUSIONS: Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery.

Animals↗
PubMed2026

Celery seed extract attenuates sarcopenic obesity and age-related sarcopenia by reducing intramuscular lipid accumulation in mice.

BACKGROUND & AIMS: Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is increasingly recognized to be influenced by metabolic disturbances associated with aging and obesity. Intramuscular lipid accumulation has emerged as a key pathological feature linking metabolic dysfunction to skeletal muscle deterioration. Celery seed extract (CSE) possesses anti-obesity, anti-inflammatory, and antioxidant properties; however, its potential role in skeletal muscle metabolism has not been well investigated. This study aimed to determine whether CSE attenuates skeletal muscle deterioration associated with obesity and aging through modulation of intramuscular lipid accumulation and related metabolic pathways. METHODS: Diet-induced obese mice and naturally aged mice were used to evaluate the effects of CSE supplementation. Skeletal muscle mass, grip strength, muscle morphology, intramuscular lipid content, mitochondrial metabolic signaling, inflammatory responses, and muscle protein turnover pathways were assessed using biochemical, molecular, and histological analyses. RESULTS: CSE supplementation significantly improved skeletal muscle mass, grip strength, and muscle fiber cross-sectional area in both obese and aged mice. These improvements were accompanied by reduced intramuscular triglyceride and cholesterol accumulation. Mechanistically, CSE improved mitochondrial metabolic signaling by activating the AMPK-PGC-1α pathway and increasing mitochondrial oxidative phosphorylation proteins. In addition, CSE suppressed inflammatory signaling pathways, including MAPK activation and NLRP3 inflammasome signaling, and improved muscle proteostasis by enhancing myogenic regulators while reducing the expression of proteolytic factors such as MuRF1, Atrogin-1, and myostatin. Correlation analyses further indicated that intramuscular lipid accumulation was closely associated with mitochondrial dysfunction, inflammatory activation, and muscle atrophy. CONCLUSIONS: These findings demonstrate that CSE alleviates skeletal muscle deterioration in both obesity- and aging-associated sarcopenia by reducing intramuscular lipid accumulation and improving mitochondrial metabolism, inflammatory responses, and muscle protein turnover. Targeting intramuscular lipid accumulation may therefore represent a promising nutritional strategy for preventing sarcopenia associated with metabolic and aging-related stress.

AMPK–PGC-1α↗
PubMed2026

EWAS in a polyphenol dense, DNA methylation-targeted, controlled diet and lifestyle study.

BACKGROUND: Dietary and lifestyle factors can influence DNA methylation patterns. We previously reported epigenetic age attenuation following a controlled study using an 8-week polyphenol-dense, DNA methylation-targeted diet and lifestyle intervention in healthy males (Methylation Diet and Lifestyle Study), with phytonutrient/polyphenol-rich foods (green tea, oolong tea, curcumin, garlic, and berries) being most predictive of this effect. METHODS: Here we conducted an epigenome-wide association study (EWAS) in 38 participants from the Methylation Diet and Lifestyle Study. The intervention included a dietary pattern intentionally rich in substrate and cofactor nutrients for methylation pathways, and components known to alter DNA-methyltransferase (DNMT) enzyme activity. In line with prior EWAS studies with small sample sizes where FDR-significant findings are unlikely, we used pre-specified nominal P-value thresholds (0.001, 0.0001) for the exploratory analyses. RESULTS: At P < 0.001 (unadjusted), 676 differentially methylated loci (DML) were identified in the intervention group versus 286 in controls. At P < 0.0001 (unadjusted), 50 DML were identified in the intervention group compared to 13 in controls. Fifteen DML were in transcription start site-proximal regions of genes including those involved in zinc homeostasis and nutrient sensing, development and pluripotency, proteostasis and genome stability, tumor suppression, and synaptic function. A group-by-time interaction analysis identified 70 intervention-specific DML at P < 0.0001, with nominal enrichment including autophagy, mTOR signaling, and chromatin remodeling pathways. A regional DMR analysis identified 128 within-group and 129 interaction-specific DMRs. DMR functional enrichment analyses revealed convergent nominal associations with lipid metabolism (alpha-linolenic acid, lipoic acid, biosynthesis of unsaturated fatty acids, PPAR signaling, cholesterol homeostasis), central energy metabolism (TCA cycle, glycolysis/gluconeogenesis, pentose phosphate, pyruvate), and nutrient sensing (PI3K-Akt, mTOR, AMPK, autophagy as well as other pathways). As expected for the limited cohort size and short intervention duration, none of the single CpG findings or enrichment analyses survived multiple test correction and are therefore considered exploratory and hypothesis-generating only. CONCLUSION: This EWAS identified a larger number of nominally changing CpGs in the intervention group compared to controls as well as biologically coherent methylation changes. These findings provide mechanistic hypotheses for previously observed epigenetic age attenuation. Replication in larger cohorts, longer intervention durations, and functional validation remain essential.

DNA methylation↗
PubMed2025

Aging and Corneal Nerve Health: Mechanisms of Degeneration and Emerging Therapies for the Cornea.

Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration.

Humans↗
PubMed2026

Nuclear export modulates TDP-43 phase transition and cytoplasmic aggregation.

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like, nuclear assemblies whose phase behavior may influence its aggregation propensity and neurotoxic activity. The mechanism(s) that modulates the transition of TDP-43 from a liquid to solid phase is poorly defined. Here we combine chemical and genome-wide genetic screenings to identify cellular factors that modulate the phase behavior of an RNA-binding defective TDP-43 mutant that mimics an Amyotrophic Lateral Sclerosis (ALS)-associated variant. Our screens uncover multiple cellular processes including RNA splicing, protein translation, proteostasis imbalance and nuclear export as TDP-43 phase regulators. Importantly, TDP-43 phase transition can be dynamically recapitulated in vitro in a semi-permeabilized cell system, which reveals that the inhibition of nuclear export reshapes the nuclear environment in favor of an RNA-dependent TDP-43 liquid-liquid phase separation (LLPS) state, which mitigates cytoplasmic TDP-43 aggregation. We validated this mechanism in a brain organoid model bearing an ALS-associated mutation, showing that nuclear export deficiency can limit pathogenic phospho-TDP-43 accumulation. These findings establish nuclear export as a key regulator of TDP-43 phase transitions and define a mechanistic framework that links altered nuclear transport and phase dynamics to TDP-43 aggregation potential.

Amyotrophic Lateral Sclerosis (ALS)↗
PubMed2026

Parietal Cortex Transcriptomics Refines Parkinson Disease GWAS Nomination and Highlights STAT3 as a Putative Upstream Glial Regulator.

Parkinson disease (PD) affects more than 1.1 million individuals in the United States and around 12 million worldwide. Although Genome Wide Association Studies (GWAS) have substantially advanced our understanding of PD genetic architecture, the regulatory mechanisms linking PD risk loci to disease-relevant gene expression remain incompletely characterized, limiting our ability to infer disease mechanisms from genetic associations. Here, we integrated disease-state parietal cortex transcriptomics with the International Parkinson's Disease Genomics Consortium (iPDGC) locus prioritization to refine PD gene nomination and identify biologically plausible candidates missed by GWAS-only approaches. Using bulk RNA-seq from 99 neuropathologically confirmed PD cases and 30 neuropathologically confirmed controls, we prioritized candidate genes across 78 loci and classified them according to concordance between genetic evidence and differential expression in diseased cortices. This integrative approach recovered candidate genes not captured by external GWAS-based prioritization methods and highlighted synaptic, lysosomal, and proteostasis pathways as major components of PD risk biology. Network and transcription factor analyses further suggested coordinated regulation of these genes, with STAT3 emerging as a putative upstream glial regulator. Together, these findings suggest that integrating disease-state transcriptomics with genetic prioritization can refine PD risk-gene nomination and uncover regulatory programs that may be missed by GWAS alone.

Journal Article↗
PubMed2025

Nuclear and cytosolic J-domain proteins provide synergistic control of Hsf1 at distinct phases of the heat shock response.

The heat shock response (HSR) is the major defense mechanism against proteotoxic stress in the cytosol and nucleus of eukaryotic cells. Initiation and attenuation of the response are mediated by stress-dependent regulation of heat shock transcription factors (HSFs). Saccharomyces cerevisiae encodes a single HSF (Hsf1), facilitating the analysis of HSR regulation. Hsf1 is repressed by Hsp70 chaperones under non-stress conditions and becomes activated under proteotoxic stress, directly linking protein damage and its repair to the HSR. J-domain proteins (JDPs) are essential for targeting of Hsp70s to their substrates, yet the specific JDP(s) regulating Hsf1 and connecting protein damage to HSR activation remain unclear. Here, we show that the yeast nuclear JDP Apj1 primarily controls the attenuation phase of the HSR by promoting Hsf1's displacement from heat shock elements in target DNA. In apj1&#x394; cells, HSR attenuation is significantly impaired. Additionally, yeast cells lacking both Apj1 and the major JDP Ydj1 exhibit increased HSR activation even in non-stress conditions, indicating their distinct regulatory roles. Apj1's role in both nuclear protein quality control and Hsf1 regulation underscores its role in directly linking nuclear proteostasis to HSR regulation. Together, these findings establish the nucleus as key stress-sensing signaling hub.

Saccharomyces cerevisiae Proteins↗
PubMed2026

Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation.

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanisms that govern the liquid-to-solid phase transition of TDP-43 remain poorly defined. Here, we combined chemical and genome-wide genetic screens to identify cellular factors that modulate the phase behavior of an RNA-binding-defective TDP-43 mutant. Our screens uncovered multiple cellular processes, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.

DNA-Binding Proteins↗
PubMed2026

Distinct molecular responses to acute cold exposure revealed by comparative transcriptomic and metabolomic profiling in the bay scallop Argopecten irradians.

Acute cold stress can elicit distinct molecular responses even when bay scallop populations show similar phenotypic outcomes. We compared a seventh-generation fast-growing bay scallop line (BS) with a commercial control population (CC) during a 72-h acute cold exposure at -1&#xa0;&#xb1;&#xa0;0.3&#xa0;&#xb0;C. RNA-seq was used as the discovery layer, representative BS cold-responsive genes were evaluated by qRT-PCR, and paired LC-MS profiles provided a comparative metabolic layer. At baseline, 138 genes differed between BS and CC; after cold exposure, 134 of these baseline differences disappeared and 61 of 65 cold-state differences newly emerged. BS showed a larger transcriptomic response magnitude than CC, with 1129 cold-responsive genes compared with 28 genes in CC, and this ordering remained robust across multiple sensitivity analyses. Survival after 72&#xa0;h was identical in BS and CC (83/90, 92.2% in each population). Biochemical responses were time-dependent and marker-specific: CAT, LZM, T-SOD and T-AOC showed population-by-time interactions, whereas GSH-Px and MDA did not, and the 72-h differences were not consistently favourable to BS. Metabolomic cold effects were strongly concordant between populations, and no feature showed a significant population-by-cold interaction. Features putatively assigned to arachidonic acid metabolism were enriched, but this provider-annotated pathway signal remains exploratory because authentic-standard confirmation was not performed. These findings indicate population-specific differences in molecular responsiveness but do not establish superior cold tolerance in BS.

Animals↗
PubMed2026

Emergent 3D genome reorganization and graded gene control from the stepwise assembly of transcriptional condensates.

Transcriptional condensates are clusters of transcription factors, coactivators, and RNA Pol II associated with gene activation, yet how they assemble and function within the cell remains unclear. Here, we show that transcriptional condensates form in a stepwise manner to enable both graded and three-dimensional (3D) gene control in the yeast heat shock response (HSR). First, the transcription factor Hsf1 (heat shock factor 1) clusters upon partial dissociation from the chaperone Hsp70. Next, the coactivator Mediator partitions following further Hsp70 dissociation and Hsf1 phosphorylation. Finally, Pol II condenses, driving emergent coalescence of HSR genes. Separation-of-function Hsf1 mutants revealed graded (non-switch-like) control of transcription and a decoupling of condensate formation and gene activation. Fully assembled HSR condensates promoted adaptive 3D genome reconfiguration, suggesting a role beyond transcription. In the HSR, differential condensation of the transcriptional machinery quantitatively tunes gene expression and qualitatively remodels the 3D genome.

3D genome↗
PubMed2026

Oncogene activation mechanism determines the limits of targeted protein degradation.

Protein degrader drugs such as PROTACs are being advanced as therapeutics targeted against oncogenic proteins. During tumorigenesis, oncogenic proteins can become constitutively activated via mechanisms including gene amplification, which increases protein production, and point mutations, which can extend protein half-life. Few experimental studies have addressed how disease-associated changes in target protein homeostasis influence PROTAC activity. We developed orthogonal methods to increase production or enhance stability of &#x3b2;-catenin, an important oncoprotein and target for degrader therapeutics, and used the dTAG system to evaluate the consequences for PROTAC activity. Stabilizing oncogenic missense mutations increase protein expression up to 5-fold but do not alter the PROTAC-imposed minimal steady-state level. In contrast, transcriptional upregulation increases both pre- and post-treatment target levels, revealing a synthesis-dependent ceiling on achievable depletion. Our results highlight distinct constraints on PROTAC activity arising from different mechanisms of oncogene activation, with potential implications for preclinical modeling, drug resistance and personalized medicine.

Humans↗
PubMed2026

Pairwise transmembrane domain insertion during multipass protein biogenesis.

The &#x223c;2,500 multipass membrane proteins encoded in the human genome are constructed mostly or entirely of transmembrane domain (TMD) pairs: exceptionally common biosynthetic units comprised of two TMDs separated by a short non-cytosolic loop. It has long been thought that each TMD of a pair sequentially enters the lipid bilayer through a lateral gate in the Sec61 protein translocation channel. Here, we show that TMD pairs can access multiple insertion routes and that most are completely impervious to small-molecule blockade of Sec61's lateral gate. Obligate use of Sec61 is seen only for exceptional cases where the translocated loop exceeds &#x223c;60 amino acids. TMD pairs with shorter loops typically use either EMC or GEL, insertase complexes of the universally conserved Oxa1 superfamily. Our results suggest that, contrary to long-held Sec61-based models, the fundamental biosynthetic unit of nearly all multipass membrane proteins uses the Oxa1 family for insertion.

Humans↗
PubMed2026

Molecular mechanism of HUWE1-HAPSTR1-USP7-mediated ubiquitin chain amplification on nuclear proteins.

Rapid protein turnover is essential for cellular stress adaptation. HUWE1 (HECT, UBA, and WWE domain containing 1), a large HECT-type E3 ligase, regulates many short-lived stress-responsive proteins, yet the mechanisms underlying its substrate selectivity remain unclear. Here, we reveal that HUWE1 functions as a ubiquitin chain amplifier that captures pre-ubiquitinated substrates and amplifies the degradation signal by assembling long ubiquitin chains containing K11-K48 branch points, a process regulated by its partners HUWE1-associated protein stress response 1 (HAPSTR1) and USP7 (ubiquitin-specific-processing protease 7). Structural and biochemical analyses show that HAPSTR1 engages HUWE1's ubiquitin-binding motifs to drive nuclear import and modulate substrate recruitment. A cryo-EM structure of the HUWE1-USP7 complex reveals a bidirectional regulatory mechanism: HUWE1 activates USP7's catalytic activity, while USP7 modulates HUWE1 conformational states. Global proteomic analyses demonstrate that this axis drives extensive remodeling of the short-lived nuclear proteome. These findings establish the HUWE1-HAPSTR1-USP7 complex as a key ubiquitin code modifier, providing a molecular rationale for HUWE1 dysregulation in neurodevelopmental disorders and cancer.

Ubiquitin-Specific Peptidase 7↗
PubMed2026

A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

Humans↗