Volume 32 Issue 9, September 2025

Post-translational modifications show mechanistic crosstalk, exemplified by the ADP-ribose–ubiquitin hybrid signal, in which one post-translational modification modifies another. This Comment highlights its discovery, mechanistic basis and functional consequences, and outlines critical questions for understanding this emerging signaling paradigm.

A recent high-resolution structure of USP30 bound to a selective inhibitor identifies a cryptic binding pocket formed through a conformational switch in the catalytic domain of the enzyme. This mechanistic insight opens a door to structure-guided design of mitophagy-enhancing compounds.

Centrosomal protein assemblies can lead to mitotic spindle dysfunction and abnormal cell division. Two studies published in this issue unveil the molecular choreography orchestrated by TRIM37 in blocking the accumulation of these structures in a remarkable fashion that resembles viral capsid recognition.

A new class of small molecular ‘glues’ selectively inhibit the BRISC deubiquitylase complex by stabilizing it in an inactive dimeric conformation. These compounds reduce inflammatory signaling by preventing deubiquitylation of an interferon receptor, and thereby offer a promising avenue for the treatment of type I interferon-driven diseases.

The Pro/N-degron E3 ligase GID4 can be harnessed for proteolysis-targeting chimera (PROTAC) applications, as demonstrated by a GID4-based bromodomain-containing protein 4 (BRD4)-targeting PROTAC, which inhibits cell proliferation and exhibits antitumor activity. Structural analysis of the GID4–PROTAC–BRD4 ternary complexes reveals plasticity in the underlying interactions, providing valuable insights into the degradation mechanism.

Autophagy is initiated by the Unc-51-like kinase protein kinase complex (ULK1C) and class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1). Here, the authors reveal the structure of the 2:1:1 core of ULK1C and its complex with PI3KC3-C1. ULK1C transitions to a 2:2:2 complex in the presence of PI3KC3-C1, suggesting a mechanism for autophagy induction.

Here, Song and Li et al. show that autophagy-related 8 (Atg8) recruits Atg1 to the surface of autophagosomes to coordinate membrane expansion of the autophagy machinery. Artificial tethering of the Atg1 kinase domain to autophagosomal membranes boosts autophagy in multiple species.

Rashan, Bartlett and colleagues show that mammalian 4-hydroxy fatty acids are primarily catabolized by ACAD10 and ACAD11 (atypical mitochondrial and peroxisomal acyl-CoA dehydrogenases, respectively) that use phosphorylation in their reaction mechanisms.

Zeinert et al. provide cryo-EM structures of the E. coli Mg²⁺ importer MgtA: unexpectedly, this P-type ATPase is a dimer with an uncommon transmembrane ion-binding site and knotted N-terminus, which are functionally important features.

Wu et al. shed light on the role of peroxisomal biogenesis factor 14 (PEX14) in peroxisomal protein import. They show that PEX14 condensates recruit the receptor PEX5 loaded with peroxisome-targeting signal 1 (PTS1) clients or PTS2 clients bound to receptor PEX7.

Köhler et al. present the crystal structure of fungal tRNA ligase Trl1-LIG bound to an activated RNA substrate, providing key insights into conserved substrate binding and activation, enzyme specificity and a tRNA substrate coordination model.

Xia et al. show how p53, guided by cis-regulatory sequences and cofactors (purine-rich element binding protein B and HOX transcript antisense RNA), orchestrates promoter-specific transcriptional regulation.

Carmona-Rosas, Li and Smith et al. show that two cell surface receptors, latrophilin and Toll-like receptor, interact in Caenorhabditis elegans and mediate strong roles in early development and morphogenesis.

Licensing of eukaryotic origins of replication with MCM double hexamers (DHs) can occur through distinct pathways. Here, Lim et al. show that in yeast, cell cycle-dependent regulation of DH formation by CDK and origin structure have co-evolved.

Khan et al. show that Sec18 uses both D1 and D2 AAA+ rings cooperatively, opening them laterally for SNARE substrate loading and for subsequent release of SNAREs.

Florez Ariza and Lue et al. use cryo-electron microscopy to investigate how the RECQL5 helicase regulates transcription. Their structural findings suggest that RECQL5 can modulate RNA polymerase II’s translocation state, potentially restarting stalled transcription.

Using cryo-electron microscopy and biochemistry, Zhang et al. reveal that the DNA helicase RECQL5 and the transcription-coupled DNA repair complex coordinate to regulate transcription elongation rates and maintain genome stability.

Naydenova, Boyle and Pathe et al. report that Shigella uses the ubiquitin E3 ligase IpaH1.4 to evade lipopolysaccharide ubiquitylation in infected cells by degrading the host E3 ligase RNF213. Using cryo-electron microscopy, they present the structural basis of this interaction and the mechanism of immune evasion.

Here, Arkinson et al. reconstitute NUB1-mediated FAT10 degradation by the human 26S proteasome and use biochemistry, cryo-EM and hydrogen–deuterium exchange to show that NUB1 acts as an ATP-independent chaperone to trap partially folded FAT10 for proteasome delivery.

Using biochemistry, chemical biology, and cryo-EM, Maiwald et al. elucidate how TRIP12 forms K29 linkages and K29/K48-linked branched ubiquitin chains, revealing a mechanism for polyubiquitylation shared by some HECT E3s.

Kazi et al. report the crystal structure of the mitochondrial deubiquitinase USP30, a clinical stage Parkinson’s disease drug target, in complex with a specific inhibitor. The authors delineate a framework for specific deubiquitinase inhibition.

Here Yeow et al. present a model in which TRIM37 regulates microtubule-organizing centers through substrate-templated activation, providing a unifying mechanism for the control of mesoscale assemblies by the TRIM family of E3 ligases.

Bellaart et al. address how the ubiquitin ligase tripartite motif-containing protein 37, the gene for which is mutated in Mulibrey nanism, uses peptide motif recognition and substrate-directed oligomerization to prevent the formation of ectopic spindle poles that cause chromosome missegregation.

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactivate BRISC, promoting interferon receptor ubiquitylation and degradation to dampen immune responses.

Here the authors show that the E3 ligase GID4 can be harnessed for targeted protein degradation and present the crystal structure of the GID4–PROTAC–BRD4 ternary complex to elucidate the underlying molecular mechanisms.