Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.

Caleb R Glassman; Kheewoong Baek; Gaopeng Hou; Qiru Zeng; Christopher Nardone; Kate B Juergens; Eric Fujimura; Colin N O'Leary; Mamie Z Li; Joao A Paulo; Eric S Fischer; Siyuan Ding; J Wade Harper; Stephen J Elledge

doi:10.1126/science.aec6299

PubMed · 42424437

Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.

Caleb R Glassman·Kheewoong Baek·Gaopeng Hou·Qiru Zeng·Christopher Nardone·Kate B Juergens·Eric Fujimura·Colin N O'Leary·Mamie Z Li·Joao A Paulo·Eric S Fischer·Siyuan Ding·J Wade Harper·Stephen J Elledge

View original source ↗Export metadata ↓

Abstract

Viruses are intracellular parasites that reprogram the host proteome to promote replication and evade immune recognition. We applied a virome-wide library of ~10,000 open reading frames to discover viral ubiquitin ligases, mapping their mechanisms of degradation and host substrates using targeted CRISPR screens and proteomics. These viral effectors could be classified as canonical ligases that mimic host E3s, hijackers that redirect host E3s, and noncanonical ligases that rewire cullin-RING ligase machinery. These diverse strategies of virus-mediated degradation converged on immune-related substrates, including JAK1 and CUL1β-TrCP, underscoring immune evasion as a major driver of viral ubiquitin ligase evolution. Our findings elucidate viral strategies for exploiting the ubiquitin-proteasome system with potential for therapeutic targeting.

Explore related subjects

Humans beta-Transducin Repeat-Containing Proteins Cullin Proteins Genome, Viral Host-Pathogen Interactions Immune Evasion Proteasome Endopeptidase Complex Proteolysis Proteomics Ubiquitin-Protein Ligases Ubiquitination Viral Proteins Viruses Cell Line, Tumor Journal Article

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Caleb R Glassman, Kheewoong Baek, Gaopeng Hou, Qiru Zeng, Christopher Nardone, Kate B Juergens, Eric Fujimura, Colin N O'Leary, Mamie Z Li, Joao A Paulo, Eric S Fischer, Siyuan Ding, J Wade Harper, Stephen J Elledge. 2026-08-20. Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.. https://doi.org/10.1126/science.aec6299

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2027

Global Genomic Surveillance.

Global genomic surveillance has emerged as a foundational pillar of public health in the twenty-first century, enabling real-time tracking of pathogen evolution and informing outbreak response. This chapter examines the strategic architecture of global genomic surveillance, focusing on its application to arboviruses such as chikungunya virus (CHIKV). It explores the integration of genomic data with epidemiological, clinical, and environmental information within a One Health framework, while addressing critical challenges in governance, equity, and interoperability. The discussion covers the entire genomic surveillance workflow, from sample collection and sequencing to bioinformatic analysis and phylogenetic inference, and highlights the transformative role of artificial intelligence (AI) in predictive surveillance. By analyzing global initiatives, operational barriers, and emerging technologies, this chapter underscores the necessity of sustainable, equitable, and interoperable genomic systems to proactively address current and future infectious disease threats.

Humans↗

PubMed2027

Systematic Dissection of Key Driver Perturbation Signatures in Single Cells via ECCITE-seq.

CRISPR screens, such as expanded CRISPR-compatible cellular indexing of transcriptomes and epitopes by sequencing (ECCITE-seq), enable the simultaneous measurement of transcriptomes, gRNA identity, and cell-surface protein expression at single-cell resolution to systematically interrogate gene function. This platform provides a powerful and scalable experimental approach for validating disease-associated regulators identified by large-scale association studies and other computational methods, including network-based analyses of multi-omics data. Here, as an example application, we describe an ECCITE-seq framework to characterize the transcriptomic consequences of perturbing multiple neuronal key driver genes associated with Alzheimer's disease (AD) in human-induced pluripotent stem cell (hiPSC)-derived neurons. More broadly, by integrating customized pooled gRNA libraries with different CRISPR effectors across multiple cell types, this approach allows for the assessment of the regulatory impact of candidate genes implicated in development and disease processes.

Humans↗

PubMed2027

Identification of Genome-Wide Chromatin Structural Aberration in Cancer by Hi-C Analysis.

Aberrant three-dimensional genome organization is a hallmark of cancer, often driving oncogene activation through mechanisms such as enhancer hijacking. High-throughput chromosome conformation capture (Hi-C) maps these interactions on a genome-wide scale. Unlike earlier dilution-based methods, in situ Hi-C performs proximity ligation within intact nuclei, minimizing random ligation noise and enabling fine-scale structure detection. This chapter describes an optimized in situ Hi-C protocol tailored for cancer cell lines using MboI digestion and biotin-mediated pull-down to generate high-complexity libraries. We further outline a computational workflow that extends beyond standard topological mapping of compartments and topologically associating domains to identify cancer-specific aberrations. Specifically, we focus on detecting chromosomal rearrangements (structural variants) and characterizing the distinct circular topology of extrachromosomal DNA. This integrated experimental and analytical framework provides the necessary tools to dissect the spatial dysregulation underlying tumor evolution.

Humans↗