TMEM165 a new player in proteoglycan synthesis: loss of TMEM165 impairs elongation of chondroitin- and heparan-sulfate glycosaminoglycan chains of proteoglycans and triggers early chondrocyte differentiation and hypertrophy.

ABSTRACT: TMEM165 deficiency leads to skeletal disorder characterized by major skeletal dysplasia and pronounced dwarfism. However, the molecular mechanisms involved have not been fully understood. Here, we uncover that TMEM165 deficiency impairs the synthesis of proteoglycans by producing a blockage in the elongation of chondroitin-and heparan-sulfate glycosaminoglycan chains leading to the synthesis of proteoglycans with shorter glycosaminoglycan chains. We demonstrated that the blockage in elongation of glycosaminoglycan chains is not due to defect in the Golgi elongating enzymes but rather to availability of the co-factor Mn²⁺. Supplementation of cell with Mn²⁺ rescue the elongation process, confirming a role of TMEM165 in Mn²⁺ Golgi homeostasis. Additionally, we

SUBMITTER: Khan S 

PROVIDER: S-EPMC8688514 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature