Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes.

[oculocutaneous albinism]

Accumulation of proteins in the endoplasmic reticulum (ER ) typically induces stress and initiates the unfolded protein response (UPR ) to facilitate recovery . If homeostasis is not restored , apoptosis is induced . However , adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress . We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca 2 )-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin . Although thapsigargin triggers UPR activation , instead of Perk-mediated phosphorylation of eIF 2 α , in Oca 2 -null melanocytes , eIF 2 α was rapidly dephosphorylated upon treatment . Dephosphorylation was mediated by the Gadd 34 -PP 1 α phosphatase complex . Gadd 34 -complex inhibition blocked eIF 2 α dephosphorylation and significantly increased Oca 2 -null melanocyte sensitivity to thapsigargin . Thus , Oca 2 -null melanocytes adapt to acute ER stress by disruption of pro-apoptotic Perk signaling , which promotes cell survival . This is the first study to demonstrate rapid eIF 2 α dephosphorylation as an adaptive mechanism to ER stress .