Loss of HD-Ptp Function Results in Lipodystrophy, Defective Cellular Signaling and Altered Lipid Homeostasis

Authors

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

Language

English

Publication Date

9-15-2024

Journal

Journal of Cell Science

DOI

10.1242/jcs.262032

PMID

39155850

PMCID

PMC11449442

PubMedCentral® Posted Date

9-27-2024

PubMedCentral® Full Text Version

Post-print

Abstract

His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) 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, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (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. The 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.

Keywords

Animals, Homeostasis, Mice, Signal Transduction, Lipodystrophy, Endosomal Sorting Complexes Required for Transport, Protein Tyrosine Phosphatases, Non-Receptor, Cholesterol, Lipid Metabolism, ErbB Receptors, Humans, Adipose Tissue, White, HD-PTP, PTPN23, ESCRT, Lipid homeostasis, Receptor signaling

Published Open-Access

yes

Recommended Citation

Schultz, Destiny F; Davies, Brian A; Payne, Johanna A; et al., "Loss of HD-Ptp Function Results in Lipodystrophy, Defective Cellular Signaling and Altered Lipid Homeostasis" (2024). Faculty, Staff and Student Publications. 5510.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5510