Distinct roles of SEC24D in procollagen quality control and trafficking

Authors

• M Sellamani
• E Makareeva
• S Omari
• L Sergey

Abstract

SEC24 family of COPII coat proteins recognize cargo for loading into endoplasmic reticulum (ER) exit sites (ERESs) and export from the ER. SEC24D deficiency causes a recessive Cole-Carpenter syndrome (CCS) type 2 characterized by distinctive facial features and osteogenesis-imperfecta-like bone pathology. A phenotypically similar, dominant CCS type 1 results from mutations in P4HB, a multifunctional ER chaperone and a Beta subunit of collagen prolyl 4-hydroxylase that recognizes unfolded chains of PC1. Both CCS1 and CCS2 mutations are expected to impair PC1 export from the ER, yet the underlying mechanisms and the relationship between P4HB and SEC24D functions have not been established. We hypothesize that SEC24D is essential for rerouting misfolded PC1 marked by bound P4HB to lysosomal degradation via ERES microautophagy. Importantly in osteoblasts, the cells produce the collagen matrix of bone. Massive PC1 synthesis by osteoblasts imposes unique requirements on secretion of properly folded PC1 molecules and degradation of misfolded ones. To test this hypothesis, we imaged COPII proteins (SEC31A, SEC24C, SEC24D), PC1, and lysosomal membrane protein LAMP1 in a human osteoblast cell line using Airyscan microscopy. We observed complete colocalization of SEC31A and SEC24C at all ERESs while SEC24D (60% homologous to SEC24C) had a different pattern with preferential localization inside lysosomal membranes. Dependence of the expression of SEC24 isoforms on osteoblast maturity and PC1 colocalization with SEC31A, SEC24C, and SEC24D suggested a distinct role of SEC24D in PC1 rerouting for degradation, supporting our hypothesis, and further looking at PC1 secretion and degradation affected by SEC24D deficiency.

Scientific Focus Area: Clinical Research

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