ER ‐to‐Golgi Blockade of Nascent Desmosomal Cadherins in SERCA2‐inhibited Keratinocytes: Implications for Darier's Disease

Abstract
Darier's disease (DD) is an autosomal dominantly inherited skin disorder caused by mutations in SERCA2, a Ca2+ pump that transports Ca2+ from the cytosol to the endoplasmic reticulum (ER). Loss of desmosomes and keratinocyte cohesion is a characteristic feature of DD. Desmosomal cadherins (DC) are Ca2+‐dependent transmembrane adhesion proteins of desmosomes, which are mislocalized in the lesional but not perilesional skin of DD. We show here that inhibition of SERCA2 by two distinct inhibitors results in accumulation of DC precursors in keratinocytes, indicating ER‐to‐Golgi transport of nascent DC is blocked. Partial loss of SERCA2 by siRNA has no such effect, implicating that haploinsufficiency is not sufficient to affect nascent DC maturation. However, a synergistic effect is revealed between SERCA2 siRNA and an ineffective dose of SERCA2 inhibitor, and between an agonist of the ER Ca2+ release channel and SERCA2 inhibitor. These results suggest that reduction of ER Ca2+ below a critical level causes ER retention of nascent DC. Moreover, colocalization of DC with ER calnexin is detected in SERCA2‐inhibited keratinocytes and DD epidermis. Collectively, our data demonstrate that loss of SERCA2 impairs ER‐to‐Golgi transport of nascent DC, which may contribute to DD pathogenesis.

Source: Traffic - January 31, 2017 Category: Research Authors: Ning Li, Moonhee Park, Shengxiang Xiao, Zhi Liu, Luis A. Diaz Tags: ORIGINAL ARTICLE Source Type: research