The E3-ome defines the human repertoire of ubiquitin E3 ligases, creating a unified resource that maps their diversity across the ubiquitin and ubiquitin-like systems. By consolidating fragmented knowledge, this framework provides a foundation for studying ubiquitin signaling and accelerating discovery.

Nature Reviews Molecular Cell Biology, Published online: 30 March 2026; doi:10.1038/s41580-026-00967-zThis Comment discusses the bidirectional interplay between STING signalling and lipid homeostasis, highlighting the emerging therapeutic relevance of this regulatory network.

To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the hu…

The E3-ome defines the human repertoire of ubiquitin E3 ligases, creating a unified resource that maps their diversity across the ubiquitin and ubiquitin-like systems. By consolidating fragmented know...

Multidomain proteins consist of folded domains connected by intrinsically disordered regions. The flexibility afforded by the disordered regions coupled to the structure and surface chemistry of folded regions allows for unique structural and functional features in these proteins. Yet how intramolecular interactions between disordered regions and folded domains affect multidomain protein structure and function remain poorly understood. Here we use a range of biophysical and computational approaches to measure the intramolecular interactions between the folded domains and disordered regions of ubiquilins (UBQLNs) - essential components of protein quality control that shuttle poly-ubiquitinated client proteins to proteasomal degradation or autophagy. Starting with the yeast UBQLN homolog Dsk2, we find that interactions between two folded domains located at the opposite ends of UBQLN bring about a closed conformation. The prevalence of this closed conformation, however, is modulated by intramolecular interactions involving the disordered regions and folded STI1 domain at the center of the protein. Simulations and analysis of UBQLN homologs across multiple eukaryotic lineages reveals that these disordered:folded domain interactions exist in some UBQLN homologs but are absent in others, indicating possible fundamental differences in function among proteins with the same multidomain architecture. ### Competing Interest Statement The authors have declared no competing interest.

Here, Deol et al. use genetic screens in gene-edited reporter cell lines to identify regulators of ferroptosis suppressor protein 1 (FSP1) expression and stability. They show that vitamin B2 metabolis...

Nuclear protein homeostasis relies on proteasome import into the nucleus. Here the authors identify how assembled human proteasomes are transported across the nuclear pore complex and reveal a mechani...

A group of accessory adapters positions the p97 adapter Ufd1 to boost substrate unfolding and subsequent proteasomal degradation.

Proteolysis-targeting chimeras (PROTACs) have transformed the concept of chemical intervention in biological systems by co-opting the ubiquitin–proteasome system to selectively degrade proteins. A key...

CRISPR–Cas9 screening identifies CLCC1 as a factor that increases neutral lipid flux to prevent hepatic steatosis and promotes nuclear pore complex assembly by promoting membrane bending and fusi...

Membrane contact sites (MCS) are dynamic regions where the membranes of two organelles come into close apposition. MCSs play many roles in cellular homeostasis by facilitating inter-organelle lipid ex...

Language production and comprehension are often studied as separate processes, but they are intertwined in naturalistic conversation. In this Review, Holler and Kuhlen summarize how visual signals, feedback and multi-party interactions contribute to language processing and require further study.

An atlas mapping organ-specific metabolite production and consumption across various pathophysiological states in pigs shows impaired metabolic activity across organs by a Western diet or hypercholest...

AbstractSummary. Lipid–protein interactions play essential roles in cellular signaling and membrane dynamics, yet their systematic characterization has lon

Regenerative medicines are headed for people with Parkinson’s disease or severe heart failure — but researchers are concerned about minimal clinical-trial data.

Polymerization-inducing chimeras are a novel bifunctional modality that uses protein symmetry to sequester targets by forming insoluble supramolecular assemblies. This approach overcomes reliance on a...

An orthosteric CSN inhibitor gains nanomolar potency via a molecular-glue mechanism, stabilizing a CSN5–N8–inhibitor complex that confers substrate-dependent inhibition despite weak free-enzyme affinity.