Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life

David R. Amici; Sammy Alhayek; Austin T. Klein; Yi Zhi Wang; Anika P. Wilen; Weimin Song; Pei Zhu; Abhishek Thakkar; McKenzi A. King; Adam W.T. Steffeck; Milad J. Alasady; Clara Peek; Jeffrey N. Savas; Marc L. Mendillo

doi:10.26508/lsa.202302370

Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life

David R. Amici, Sammy Alhayek, Austin T. Klein, Yi Zhi Wang, Anika P. Wilen, Weimin Song, Pei Zhu, Abhishek Thakkar, McKenzi A. King, Adam W.T. Steffeck, Milad J. Alasady, Clara Peek, Jeffrey N. Savas, Marc L. Mendillo^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as up-stream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.

Original language	English (US)
Article number	e202302370
Journal	Life science alliance
Volume	7
Issue number	5
DOIs	https://doi.org/10.26508/lsa.202302370
State	Published - May 2024

Funding

Total and diglycine proteomic experiments were performed in collaboration with the Thermo Fisher Scientific Center for Multiplexed Proteomics at Harvard Medical School (https://tcmp.hms.harvard.edu). Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. This work was supported by NIHF30CA264513 and NIHT32GM008152 to DR Amici, NIHR01AG078796 to JN Savas, and NIH1R01GM144617-01 to ML Mendillo, and American Cancer Society ABOA Impact RSG-22-086-01-TBE to ML Mendillo.

ASJC Scopus subject areas

Ecology
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Plant Science
Health, Toxicology and Mutagenesis

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10.26508/lsa.202302370

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title = "Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life",

abstract = "The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as up-stream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.",

author = "Amici, {David R.} and Sammy Alhayek and Klein, {Austin T.} and Wang, {Yi Zhi} and Wilen, {Anika P.} and Weimin Song and Pei Zhu and Abhishek Thakkar and King, {McKenzi A.} and Steffeck, {Adam W.T.} and Alasady, {Milad J.} and Clara Peek and Savas, {Jeffrey N.} and Mendillo, {Marc L.}",

note = "Publisher Copyright: {\textcopyright} 2024 Amici et al.",

year = "2024",

month = may,

doi = "10.26508/lsa.202302370",

language = "English (US)",

volume = "7",

journal = "Life science alliance",

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T1 - Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life

AU - Amici, David R.

AU - Alhayek, Sammy

AU - Klein, Austin T.

AU - Wang, Yi Zhi

AU - Wilen, Anika P.

AU - Song, Weimin

AU - Zhu, Pei

AU - Thakkar, Abhishek

AU - King, McKenzi A.

AU - Steffeck, Adam W.T.

AU - Alasady, Milad J.

AU - Peek, Clara

AU - Savas, Jeffrey N.

AU - Mendillo, Marc L.

PY - 2024/5

Y1 - 2024/5

N2 - The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as up-stream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.

AB - The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as up-stream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.

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Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life

Abstract

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