HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

ABSTRACT: HUWE1 is a large, enigmatic HECT domain ubiquitin ligase implicated in the degradation of numerous substrates and regulating diverse pathways including DNA repair, apoptosis, and differentiation. However, the mechanism by which HUWE1 acts in a pleiotropic manner to regulate a myriad of substrates is unknown. Recent work has established a physical and genetic interaction between HUWE1 and C16orf72/HAPSTR1, suggesting that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is both a HUWE1 substrate, and is required to localize HUWE1 to the nucleus. Quantitative proteomics across diverse cell types reveals that HUWE1 substrates are largely context specific. Transcriptomics following HUWE1 or HAPSTR1 loss of function reveals a broad transcriptional stress response. We show that nuclear HUWE1 impacts stress signaling pathways, including p53 and NFkB-mediated signaling, and is required for cell proliferation. Together, these data define a critical role for nuclear HUWE1 function that is dependent on HAPSTR1.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD041591 | Pride | 2023-05-14

REPOSITORIES: Pride