ubiquitinlike

Ubiquitin-like proteins (UBLs) are a family of small proteins that resemble ubiquitin and can be covalently attached to other proteins or molecules to regulate their function, localization, stability, or interactions. Like ubiquitin, UBLs are processed and conjugated through a ubiquitin-like enzymatic cascade, but they typically regulate distinct cellular processes and target different substrates.

Prominent members of the UBL family include SUMO (small ubiquitin-like modifier), NEDD8, ISG15, UFM1, FAT10, and the Atg8/Atg12 family involved in autophagy. SUMO and NEDD8 modify numerous substrates to influence transcription, signaling, and proteolysis; ISG15 is induced by interferons and participates in antiviral responses; UFM1 and FAT10 have roles in stress responses and protein turnover; Atg8/Atg12 proteins are central to autophagy. Each member can alter protein activity, interactions, or localization without necessarily marking the substrate for degradation.

Conjugation typically involves an enzymatic cascade with an E1 activating enzyme, an E2 conjugating enzyme, and often an E3 ligase that recognizes specific substrates. UBLs are usually synthesized as precursor proteins that must be processed to reveal a C-terminal di-glycine motif required for conjugation. Reversal of the modification is achieved by specific deconjugating proteases, restoring the substrate’s original state.

The ubiquitin-like system expands the scope of post-translational regulation beyond ubiquitin, enabling refined control of cellular processes such as transcription, DNA repair, cell cycle progression, protein trafficking, autophagy, and immune responses. Structural similarity to ubiquitin underpins their shared chemistry, while functional diversity reflects their specialized roles in cellular homeostasis.