Life would not exist without the ability to adapt to stimuli and to maintain homeostasis. Ubiquitin is a key cog in the regulation of signaling cascades and mechanisms of quality control. Ubiquitin can tag proteins and, as we are rapidly learning, other biomolecules. Becoming ubiquitylated canonically destines proteins for proteasomal degradation or constitutes a signaling event, which appears to also be a major outcome of non-protein ubiquitylation. Nature Structural & Molecular Biology (NSMB) has sought to feature state-of-the-art studies on posttranslational modifications and ubiquitylation (Nat. Struct. Mol. Biol. 31, 203–204; 2024). In this issue, we build on this aspiration and turn our focus to studies on ubiquitylation and degradation, illustrated on our cover by a school of fish reminiscent of the proteasomal barrel.

The clinical importance of understanding the molecular rules and grammar of the writers (E1–E2–E3 enzymes), erasers (deubiquitylating enzymes, DUBs) and readers of ubiquitylation is evident in the now major field of targeted protein degradation (TPD). Academic labs and pharmaceutical companies have been striving to generate novel molecular glues and proteolysis targeting chimeras (PROTACs) and to expand the arsenal of E3 ligases that can be functionalized to degrade otherwise difficult-to-target substrates. In this issue of NSMB, work from Li, Bao, Sun, Ge et al. unveils how the E3 ligase GID4 can be leveraged via custom PROTACs to target substrates of clinical importance. In an accompanying Research Briefing, the authors explain the origin and potential impact of their study.

Parallel to the efforts of developing new TPD-related tools, DUBs constitute themselves targets that are garnering attention for clinical applications. In this issue, Chandler et al. describe inhibitors termed BLUEs that selectively inactivate the DUB BRISC (BRCC36 isopeptidase complex), thereby increasing the degradative ubiquitylation of interferon receptors and moderating immune responses. The authors elaborate on the implications of their findings in a Research Briefing. Separately, Kazi et al. present a ubiquitin-specific protease 30 (USP30) inhibitor and mechanistically delineate its action, which bears implications for the modulation of USP30-mediated mitophagy and the development of selective inhibitors for other USP DUBs. In an accompanying News & Views, Fitzgerald and Bremm highlight the relevance of the work to mitophagy.

The proteasome is the canonical effector of degradative ubiquitylation. A study from Maiwald et al. explains how the TRIP12 HECT ligase deposits branched K29/K48 polyubiquitin chains of increased degradative potential on substrates. However, the proteasome is versatile and can degrade targets even in the absence of ubiquitylation. A separate body of work from Arkinson et al. delineates how NUB1–FAT10 interactions trap the ubiquitin-like modifier FAT10 in an unfolded state and allow FAT10-ylated proteins to be degraded by the proteasome independently of both ubiquitin and p97. In a Picture Story, we highlight the uniqueness of the proteasome and the other proteostatic machineries in human oocytes, an exciting area of research of fundamental importance, with implications for medicine and public health.

Mechanistically understanding how ubiquitylation-related enzymes operate may provide insight into the basis of clinical conditions, as demonstrated by two back-to-back studies investigating how TRIM37, an E3-ligase implicated in Mulibrey nanism and cancer, targets noncentrosomal microtubule-organizing centers. Work from Yeow et al. delineates how TRIM37 is catalytically activated when centrosomal proteins form mesoscale-size assemblies. An independent manuscript from Bellaart, Brambila, Xu et al. presents concordant findings and demonstrates the importance of TRIM37 oligomerization to degrade aberrant centrobin condensates. Renata Basto contextualized the combined results in a News & Views.

On the front of non-protein ubiquitylation, a study from Naydenova, Boyle, Pathe et al. advances our understanding of RNF213-dependent lipopolysaccharide ubiquitylation and how Shigella flexneri antagonizes this host-protective mechanism. Somewhat ironically, these bacteria use IpaH1.4 to hijack the ubiquitylation potential of protectors, such as RNF213 and LUBAC, to degrade them and remove them from the picture. In an interesting Comment, Chatrin, Zhu and Ahel discuss our emerging understanding and the potential implications of ADP-ribosylated ubiquitin and ubiquitylated ADP-ribose on substrates.

Beyond the realm of ubiquitin and protein degradation, this issue features interesting discoveries on autophagy, cellular metabolism, protein trafficking, organelles, chromatin, transcription, DNA replication and RNA metabolism. While we are committed to publishing work that advance our understanding of ubiquitylation, molecular modifications and protein homeostasis in diverse contexts, the content of this issue also reflects our broad scope. We thank our authors for selecting NSMB for exciting work that illuminate the details of molecular and cellular processes, as well as our readers for turning to our pages for new structural and molecular biology content. We hope that you enjoy exploring this issue.