E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation ( , ). Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension ( , ). Ubiquitinates NOS1 in concert with Hsp70 and Hsp40 . Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90 ( ). Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation (, ). Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome . Mediates polyubiquitination of CYP3A4 . Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation . Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation . Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B-dependent manner . Catalyzes monoubiquitination of SIRT6, preventing its degradation by the proteasome . Likely mediates polyubiquitination and down-regulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity . Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation . May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation . Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation .
Subcellular locations: Cytoplasm, Nucleus
Translocates to the nucleus in response to inflammatory signals in regulatory T-cells (Treg).
Expressed in differentiated myotubes (at protein level) . Highly expressed in skeletal muscle, heart, pancreas, brain and placenta (, ). Detected in kidney, liver and lung (, ).