STUB1 Protein, Human

STUB1 Protein, an E3 ubiquitin-protein ligase, plays a pivotal role in targeting misfolded chaperone substrates for proteasomal degradation, collaborating with ATXN3 to regulate the ubiquitin chain length attached to STUB1 substrates and prevent further chain extension. It ubiquitinates NOS1 in conjunction with Hsp70 and Hsp40, modulating the activity of key chaperone complexes such as Hsp70, Hsc70, and Hsp90. Additionally, STUB1 mediates the transfer of non-canonical short ubiquitin chains to HSPA8 without affecting its degradation. The protein is involved in base-excision repair by catalyzing polyubiquitination of DNA polymerase beta (POLB), amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB degradation. STUB1 also participates in the polyubiquitination of CYP3A4, ubiquitinates EPHA2 to potentially regulate receptor stability, acts as a co-chaperone for HSPA1A and HSPA1B, and negatively regulates TGF-beta signaling by modulating SMAD3 levels via ubiquitin-mediated degradation. Furthermore, STUB1 contributes to the degradation of FOXP3, SIRT6, and RIPK3, and likely downregulates PD-L1/CD274 plasma membrane expression. Its diverse functions underscore its significance in cellular homeostasis and immune regulation.