Endoplasmic reticulum-associated degradation of the mouse PC1/3-N222D hypomorph and human PCSK1 mutations contributes to obesity

International Journal of Obesity : Journal of the International Association for the Study of Obesity
P StijnenJ W Creemers

Abstract

The proprotein convertase 1/3 (PC1/3), encoded by proprotein convertase subtilisin/kexin type 1 (PCSK1), cleaves and hence activates several orexigenic and anorexigenic proproteins. Congenital inactivation of PCSK1 leads to obesity in human but not in mice. However, a mouse model harboring the hypomorphic mutation N222D is obese. It is not clear why the mouse models differ in phenotype. Gene expression analysis was performed with pancreatic islets from Pcsk1(N222D/N222D) mice. Subsequently, biosynthesis, maturation, degradation and activity were studied in islets, pituitary, hypothalamus and cell lines. Coimmunoprecipitation of PC1/3-N222D and human PC1/3 variants associated with obesity with the endoplasmic reticulum (ER) chaperone BiP was studied in cell lines. Gene expression analysis of islets of Pcsk1(N222D/N222D) mice showed enrichment of gene sets related to the proteasome and the unfolded protein response. Steady-state levels of PC1/3-N222D and in particular the carboxy-terminally processed form were strongly reduced in islets, pituitary and hypothalamus. However, impairment of substrate cleavage was tissue dependent. Proinsulin processing was drastically reduced, while processing of proopiomelanocortin (POMC) to adreno...Continue Reading

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Citations

Aug 30, 2018·Physiological Reviews·Erika HarnoAnne White
May 18, 2016·Endocrine Reviews·Pieter StijnenJohn W M Creemers
Sep 14, 2018·Experimental & Molecular Medicine·Ye Ran YoonJa-Hyun Baik
Mar 15, 2018·Endocrine·Antonella SestaFrancesca Pecori Giraldi
Aug 18, 2020·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·David R PowellRobert Brommage
Jan 1, 2021·Endocrine Reviews·Manita Shakya, Iris Lindberg
Aug 2, 2021·Endocrinology·Iris Lindberg, Lloyd D Fricker

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