ER-to-Golgi blockade of nascent desmosomal cadherins in SERCA2-inhibited keratinocytes: Implications for Darier's disease.
Darier's disease (DD) is an autosomal dominantly inherited skin disorder caused by mutations in sarco/endoplasmic reticulum Ca2+-ATPase 2 (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 2 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.
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Ning
N
Li
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Moonhee
M
Park
Department of Dermatology, The Second Hospital, Xi-An Jiaotong University, People's Republic of China.
Shengxiang
S
Xiao
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Zhi
Z
Liu
Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Luis A
LA
Diaz
D002118:Calcium / Q000378:metabolism; D037281:Calnexin / Q000378:metabolism; D002478:Cells, Cultured; D007644:Darier Disease / Q000378:metabolism*; D051181:Desmosomal Cadherins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*
D051181:Desmosomal Cadherins; D037281:Calnexin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D002118:Calcium

SERCA2 calcium pump; Darier disease; ER-to-Golgi blockade; desmosomal adhesion; desmosomal cadherins; keratinocytes