Loss of HD-PTP function results in lipodystrophy, defective cellular signaling, and altered lipid homeostasis

Destiny F Schultz; Brian A Davies; Johanna A Payne; Cole P Martin; Annabel Y Minard; Bennett G Childs; Cheng Zhang; Karthik B Jeganathan; Ines Sturmlechner; Thomas A White; Alain de Bruin; Liesbeth Harkema; Huiqin Chen; Michael A Davies; Sarah Jachim; Nathan K LeBrasseur; Robert C Piper; Hu Li; Darren J Baker; Jan van Deursen; Daniel D Billadeau; David J Katzmann

doi:10.1242/jcs.262032

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Loss of HD-PTP function results in lipodystrophy, defective cellular signaling, and altered lipid homeostasis

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Loss of HD-PTP function results in lipodystrophy, defective cellular signaling, and altered lipid homeostasis

Destiny F Schultz, Brian A Davies, Johanna A Payne, Cole P Martin, Annabel Y Minard, Bennett G Childs, Cheng Zhang, Karthik B Jeganathan, Ines Sturmlechner, Thomas A White, …

Journal of cell science, Vol.137(18), jcs262032

09/15/2024

DOI: 10.1242/jcs.262032

PMCID: PMC11449442

PMID: 39155850

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Abstract

His Domain Protein Tyrosine Phosphatase (HD-PTP) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, PI3K/AKT and RTKs such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. ESCRT components Vps4 and HRS have previously been implicated in cholesterol homeostasis, thus these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.His Domain Protein Tyrosine Phosphatase (HD-PTP) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, PI3K/AKT and RTKs such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. ESCRT components Vps4 and HRS have previously been implicated in cholesterol homeostasis, thus these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.

HD-PTP

PTPN23

ESCRT

Lipid homeostasis

Receptor signaling

Details

Title: Subtitle: Loss of HD-PTP function results in lipodystrophy, defective cellular signaling, and altered lipid homeostasis
Creators: Destiny F Schultz - Mayo Clinic
Brian A Davies - Mayo Clinic
Johanna A Payne - Mayo Clinic
Cole P Martin - Mayo Clinic
Annabel Y Minard - University of Iowa
Bennett G Childs - Mayo Clinic in Florida
Cheng Zhang - Mayo Clinic
Karthik B Jeganathan - Mayo Clinic in Florida
Ines Sturmlechner - Mayo Clinic in Florida
Thomas A White - Mayo Clinic in Florida
Alain de Bruin - University Medical Center Groningen
Liesbeth Harkema - Utrecht University
Huiqin Chen - The University of Texas MD Anderson Cancer Center
Michael A Davies - The University of Texas MD Anderson Cancer Center
Sarah Jachim - Mayo Clinic
Nathan K LeBrasseur - Mayo Clinic in Florida
Robert C Piper - University of Iowa
Hu Li - Mayo Clinic
Darren J Baker - Mayo Clinic
Jan van Deursen - Mayo Clinic
Daniel D Billadeau - Mayo Clinic
David J Katzmann - Mayo Clinic
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.137(18), jcs262032
DOI: 10.1242/jcs.262032
PMID: 39155850
PMCID: PMC11449442
NLM abbreviation: J Cell Sci
ISSN: 1477-9137
eISSN: 1477-9137
Publisher: COMPANY BIOLOGISTS LTD
Grant note: Dr Miriam and Sheldon G. Adelson Medical Research Foundation: T32DK124190 American Cancer Society: P50CA221703
This work was funded by National Institutes of Health (NIH) (R01GM116826 awarded to D.J.K.) . D.F.S. is supported by the NIH (R25GM55252 and T32DK124190) . M.A.D. is supported by the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH (NCI; P50CA221703) , the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. Deposited in PMC for release after 12 months.
Language: English
Electronic publication date: 08/19/2024
Date published: 09/15/2024
Academic Unit: Molecular Physiology and Biophysics; Medicine Administration; Internal Medicine
Record Identifier: 9984699523202771

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