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.

Author contributions

Conceptualization: D.F.S., B.A.D., D.J.K.; Methodology: D.F.S., B.A.D., D.J.B., J.v.; Validation: D.F.S., B.A.D.; Formal analysis: D.F.S., C.Z., H.C.; Investigation: D.F.S., B.A.D., J.A.P., C.P.M., A.Y.M., B.G.C., T.W., A.d., L.H., S.J.; Resources: K.B.J., I.S., M.A.D., N.K.L., R.C.P., H.L., D.J.B., J.v., D.D.B.; Writing - original draft: D.F.S.; Writing - review & editing: D.F.S., B.A.D., R.C.P., D.D.B., D.J.K.; Visualization: D.F.S., B.A.D.; Supervision: D.J.K.; Funding acquisition: D.J.K.

Funding

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.

Data availability

All relevant data can be found within the article and its supplementary information.

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