STIP1 homology and U-box containing protein 1 (STUB1) (CHIP)

STIP1 homology and U-box containing protein 1 (CHIP), also known as STUB1, is a multifunctional protein that serves as a critical link between the molecular chaperone system and the ubiquitin-proteasome system (UPS) [UniProt: Q9UNE7]. It functions as both a co-chaperone, interacting with heat shock proteins HSP70 and HSP90 via its TPR domain, and an E3 ubiquitin-protein ligase that targets chaperone-bound substrates for degradation via its U-box domain [PubMed: 10675341]. By facilitating the ubiquitination of misfolded or damaged proteins, CHIP maintains cellular proteostasis and prevents the formation of toxic aggregates [PubMed: 21859363]. This function is particularly relevant in neurodegenerative diseases like Alzheimer's and Parkinson's, where CHIP helps clear pathogenic proteins [PubMed: 21859363]. In oncology, CHIP's role is complex; it can act as a tumor suppressor by degrading oncogenic proteins like ErbB2 or, in some contexts, promote tumor growth by targeting tumor suppressors [PubMed: 24553120]. CHIP also regulates the heat shock response by modulating the stability of Heat Shock Factor 1 (HSF1) [PubMed: 11585820]. Current therapeutic interest focuses on leveraging CHIP as an E3 ligase for Proteolysis Targeting Chimeras (PROTACs) to induce the degradation of specific disease-causing proteins [PubMed: 31112123]. Additionally, small molecule modulators are being explored to enhance CHIP activity in protein-misfolding disorders [PubMed: 31112123]. Its broad expression and central role in proteostasis present both opportunities and challenges for drug development [PubMed: 21859363].

Other names

STUB1Carboxy terminus of HSP70-interacting proteinCLL-associated antigen KW-8Antigen NY-CO-7SDCCAG7E3 ubiquitin-protein ligase STUB1

CHIP acts as an E3 ubiquitin ligase that attaches ubiquitin chains to substrates presented by HSP70/HSP90 chaperones, signaling them for proteasomal degradation [PubMed: 10675341]. It also regulates the activity of the heat shock response by modulating the turnover of Heat Shock Factor 1 (HSF1) [PubMed: 11585820].