Proteomics

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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): timsTOF Pro 2

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD041595 | Pride | 2023-05-14

REPOSITORIES: Pride

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HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways.

Monda Julie K JK   Ge Xuezhen X   Hunkeler Moritz M   Donovan Katherine A KA   Ma Michelle W MW   Jin Cyrus Y CY   Leonard Marilyn M   Fischer Eric S ES   Bennett Eric J EJ  

Cell reports 20230509 5


HUWE1 is a large, enigmatic HECT-domain ubiquitin ligase implicated in the regulation of diverse pathways, including DNA repair, apoptosis, and differentiation. How HUWE1 engages its structurally diverse substrates and how HUWE1 activity is regulated are unknown. Using unbiased quantitative proteomics, we find that HUWE1 targets substrates in a largely cell-type-specific manner. However, we identify C16orf72/HAPSTR1 as a robust HUWE1 substrate in multiple cell lines. Previously established physi  ...[more]

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