E3 ubiquitin-protein ligase CHIP; antigen NY-CO-7; CLL-associated antigen KW-8; carboxy terminus of Hsp70-interacting protein; STIP1 homology & U box-containing protein 1 (STUB1 CHIP PP1131)

Function

• E3 ubiquitin protein ligase activity
  • targets misfolded chaperone substrates towards proteasomal degradation
  • mediates transfer of non-canonical short ubiquitin chains to HSPA8 without effect on HSPA8 degradation
  • ubiquitinates NOS1 in concert with Hsp70 & Hsp40
  • mediates polyubiquitination of DNA polymerase beta (POLB) at Lys-41, Lys-61 & Lys-81, thus playing a role in base-excision repair
    • catalyzes polyubiquitination by amplifying HUWE1/ARF-BP1- dependent monoubiquitination, leading to POLB-degradation by the proteasome
  • mediates polyubiquitination of CYP3A4
  • ubiquitinates EPHA2 & may regulate the receptor stability & activity through proteasomal degradation
• modulates activity of several chaperone complexes,
  • Hsp70, Hsc70, Hsp90
  • collaborates with ATXN3 in the degradation of misfolded chaperone substrates
  • ATXN3 restricts the length of ubiquitin chain attached to STUB1/CHIP substrates & preventing further chain extension
• occurs in a ternary complex containing STUB1, HSPA1A, HSPBP1
• auto-ubiquitinated (in vitro)
  • monoubiquitinated at Lys-2 following cell stress by UBE2W, promoting the interaction with ATXN3 (putative)
  • auto-ubiquitination mediated by UBE2D1 & UBE2D2
• phosphorylated upon DNA damage, probably by ATM or ATR
• interacts with BAG2, UBE2D1, UBE2D2, UBE2D3, HSPA8, HSPA1A
• interacts (via TPR repeats) with HSP90AA1
• interacts (when monoubiquitinated) with ATXN3
• interacts with UBE2W
• interacts (via the U-box domain) with the UBE2V2-UBE2N heterodimer
  • the complex has a specific Lys-63-linked polyubiquitination activity
• interacts with DNAJB6

Structure

• the TPR domain is essential for ubiquitination mediated by UBE2D1
• contains 3 TPR repeats
• contains 1 U-box domain

Compartment

cytoplasm

Alternative splicing

named isoforms=2

Expression

• expressed in skeletal muscle, heart,pancreas, brain, placenta > kidney, liver, lung

Pathology

• antibodies against STUB1 are found in patients with chronic lymphocytic leukemia (CLL) & in colorectal cancer

More general terms

• nuclear protein
• zinc finger protein
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=10273
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:10273
• OMIM: https://mirror.omim.org/entry/607207
• UniProt: http://www.uniprot.org/uniprot/Q9UNE7.html