Essays in biochemistry最新文献

SUMOylation - a protein post-translational modification (PTM) related to ubiquitylation - involves the reversible covalent attachment of the small ubiquitin-like modifier (SUMO) to proteins. During the conjugation and deconjugation cycle, SUMO is recognised and positioned by various enzymes through specific non-covalent interactions. This review discusses the core interactions with the SAE2 subunit of the SUMOspecific heterodimeric E1 enzyme SAE1:SAE2, the SUMO E2 enzyme UBC9 and the SUMO-specific proteases of the SENP family and USPL1. We describe the evolutionary origins of these interactions and their structural basis; moreover, as SUMO:enzyme interactions are generally similar in their overall outline to those between ubiquitin and its specific enzymes, we highlight these similarities, as well as the differences. All of the mentioned interactions use a similar surface on SUMO, which is distinct from the groove that binds SUMO-interacting motifs (SIMs), meaning that while the enzyme interactions are mutually exclusive, each is compatible with simultaneous SIM binding. This review is accompanied by another in the same issue that focuses on interactions with SUMO E3 ligases and downstream effectors of SUMOylation, together providing comprehensive coverage of the non-covalent interactions formed by SUMO proteins.

Inositol hexakisphosphate (IP6) is an endogenous organic molecule present in eukaryotes. First characterized as a phosphorus-storage metabolite, it has been subsequently discovered to play a role in modulating a multitude of different biological pathways. Here, we provide a concise overview of the involvement of IP6 in the ubiquitin-proteasome system (UPS). As an allosteric regulator, a molecular glue, and a potential prosthetic group, IP6 directly impacts the activities of multiple major UPS components. We specifically highlight the structural mechanisms through which IP6 binds to individual proteins or multi-protein complexes to control their functions. The serendipitous discovery of IP6 in various protein structures raises questions about the prevalence, identity, and regulation of soluble inositol polyphosphates in the UPS, which have potential translational implications.

Ubiquitin (Ub) and ubiquitin-like proteins (UBLs) are central regulators of cell signalling, with roles spanning proteasomal degradation, immune defence, DNA repair, autophagy, and the stress response. Their conserved β-grasp fold provides a remarkably versatile protein architecture that can be redeployed across diverse signalling pathways and modulated in disease contexts. Conjugation and removal through dedicated E1-E2-E3 and protease systems generate a rich regulatory code, further diversified by chain topology, hybrid architectures, and emerging non-canonical modifications. This special issue highlights recent advances in Ub and UBL biology, from specialised UBL pathways to host-pathogen interactions and non-protein conjugation events, as well as translational applications such as targeted protein degradation. Together, these reviews showcase the breadth, adaptability, and therapeutic potential of these small but powerful modifiers.

COP9 signalosome (CSN) is a representative of the ZOMES complexes, which further consist of the 26S proteasome LID and the eukaryotic translation initiation factor 3 (eIF3), key players in proteostasis. Whereas the eIF3 complex has a role in general translation initiation, the LID, as part of the regulatory particle of the 26S proteasome, is the main cellular proteolytic machinery, specifically degrades ubiquitylated substrates. Interestingly, CSN is associated with the production of ubiquitylated substrates. Contrary to its paralogous complexes, CSN appears as variants. Our interest mainly lies in the variants CSNCSN7A and CSNCSN7B. The CSN variants form stable complexes with cullin-RING-ubiquitin ligases (CRLs). While CSNCSN7A preferentially interacts with CRL3, CSNCSN7B binds to CRL4A. CSNCSN7A-CRL3 and CSNCSN7B-CRL4A complexes are stored in human cells as latent complexes. During adipogenesis in LiSa-2 model preadipocytes, the complexes are integrated into different functions. CSNCSN7A-CRL3 complexes are recruited by rat sarcoma-related small GTPase 18 to the membrane of lipid droplets, where they are neddylated. CSNCSN7B-CRL4A complexes lose their substrate receptor and stop degrading p27, causing cell cycle arrest necessary for adipogenesis. The C-terminal approximately 60 amino acids of CSN7A and CSN7B are essential for the specific binding to CRLs. Without C-termini, CSNCSN7A1-200 and CSNCSN7B1-200 lose CRL3 or CRL4A and their function. CSN-CRL complexes are degraded by a selective macroautophagic pathway. In the presence of the specific inhibitor CSN5i-3, the appearance of ubiquitylated CSN-CRL complexes was detected in cells. Nonfunctioning CSN-CRL particles are fixed as cargo before forming vesicles as autophagosomes following degradation via lysosome.

PSMD9/Nas2/Bridge-1 is one of the assembly chaperones of the 19S regulatory particle of the eukaryotic proteasome. While this is among PSMD9's well-recognized roles, the role of PSMD9 in cancer proteasome assembly/disassembly and activity, as a key factor in the ubiquitination and degradation of proteins by the proteasome, unfolded protein response, and proteostasis, nucleolar organization, are some of the recent findings. Several unbiased screening, high-throughput studies, genome-wide association studies (GWAS) have found surprising associations and potential roles for PSMD9 in a variety of diseases or conditions. Although in a majority of these cases the mechanism remains unclear, it is important to take note that this multi-functional protein, in the absence of any enzymatic role, relies primarily on its ability to interact with other proteins and biomolecules in the cells. A surprising range of proteins that associate with PSMD9 discovered by the structure-guided approaches overlaps with many different functions associated with this protein or the proteasome in literature. Collective evidence also points to the possibility that PSMD9 could be an Achilles' heel in some of the solid cancers.

Ubiquitin (Ub) and Ub-like (Ubl) signaling processes regulate broad aspects of eukaryotic cellular biology. Conserved sets of enzymes control the covalent attachment of Ub/Ubl onto proteins, and disruption of these highly regulated processes contributes to diseases including cancer and neurodegeneration. Aspects of Ub/Ubl signaling are central to the innate immune response to infectious pathogens. As such, pathogens such as viruses and bacteria have evolved sophisticated mechanisms to hijack and dysregulate the homeostasis of Ub/Ubl signaling. Pathogenic manipulation of the host Ub system is well studied, with multiple classes of secreted bacterial effector proteins discovered that regulate either Ub itself or the enzymes required for substrate ubiquitylation. While much less is known about the control of host Ubl signaling processes by pathogens, recent discoveries indicate that they, too, are hijacked during infection. The number of Ubl manipulators secreted by bacterial pathogens is likely to increase in the coming years as methods to identify and characterize bacterial effectors advance. This review highlights the current knowledge on bacterial manipulation of Ubl signaling, including SUMO, NEDD8, ISG15, UFM1, FAT10, and LC3.

Molecular glue degraders (MGDs) are small molecules that promote interactions between an E3 ligase and a target protein, reconfiguring recognition to trigger proteasome-mediated degradation. Their discovery has so far been largely serendipitous - either recognized in retrospect or uncovered through 'needle-in-a-haystack' screening - but systematic strategies are beginning to emerge. This review frames two complementary routes for discovery. The first views MGDs as modular - typically anchored on either the ligase or the target - which allows the chemical search space to be biased toward such anchoring. Ligase-directed strategies derivatize known ligase binders, as demonstrated for cereblon (CRBN) and now beyond. Conversely, recent target-directed strategies remodel inhibitors into glues through solvent-exposed elaboration, effectively inverting the classical design paradigm. Both approaches tilt discovery toward chemotypes more likely to yield glue activity. Second, biology provides its own guideposts: certain protein pairs appear especially predisposed to stabilization. Endogenous degrons, mutational lesions, and transferable 'glueprints' of surface topology all point to contexts in which small molecules might act as functional surrogates - repairing hypomorphs, mimicking hypermorphs, or creating neomorphs. MGDs, therefore, exemplify how small molecules can reprogram recognition logic by transforming latent compatibilities into selective degradation. Together, these insights help rationalize past discoveries and suggest possible blueprints for more systematic ones ahead.

Among the ubiquitin-like superfamily, small ubiquitin-like modifiers (SUMOs) are the most well-understood. However, in comparison with the prototypical small modifier ubiquitin, our understanding of the SUMO system lags. SUMOylation is often characterised as 'simple' in comparison with ubiquitination, with fewer SUMO-specific writers, readers and erasers compared with the ubiquitin machinery. A key divergence between ubiquitin and SUMO is that the SUMOylation system utilises a group of related SUMOs (SUMO1- 5), each possessing distinct functions. SUMO paralogs share conjugation, recognition and deconjugation machinery, yet signalling can employ each to perform specific cellular functions. This illustrates a complex layer of molecular discrimination that is far from simple. The repair of DNA double-stranded breaks (DSBs) - highly toxic DNA lesions generated from both endogenous and external sources - serves as a fascinating exemplar of specificity in SUMO signalling. This review focuses on how signalling specificity is achieved during SUMO-DSB repair. Examples of how different branches of SUMO signalling can direct discrete DSB-repair outcomes through modulation of key repair factors, including the RAP80-BRCA1-A complex, RNF168 and CtIP, are described in further detail.

Ubiquitin-fold modifier 1 (UFM1) is a small protein that functions as a ubiquitin-like modifier attached to other proteins to alter their behavior. Although less famous than ubiquitin, UFM1 has gained attention as a key regulator of proteostasis (protein homeostasis) in the cell. Notably, the endoplasmic reticulum (ER) has emerged as the central stage for UFM1's activity. UFM1 was initially recognized for its role in the ER stress response, and we now know it orchestrates two critical quality-control processes at the ER: ribosome-associated quality control and selective autophagy of the ER. Together, these mechanisms ensure that the cell can cope with misfolded proteins and stalled ribosomes, maintaining the health of the ER and the proteins it produces. In this review, we will explore how UFM1 works at the ER, how its components are regulated during stress, how it facilitates both immediate quality control and longer-term ER turnover, and how disruptions in this system lead to disease, especially in the nervous system.

Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.