Exit from the Endoplasmic Reticulum (ER) of newly synthesized proteins is mediated by COPII vesicles that bud from the ER at the ER Exit Sites (ERESs). Disruption of ER homeostasis causes accumulation of unfolded and misfolded proteins in the ER. This condition is referred as ER stress. Several evidences suggest a link between the ER stress and the vesicular trafficking within of the early secretory pathway. Previously, we demonstrated that ER Stress rapidly impairs the anterograde transport to the Golgi complex and the formation of COPII vesicles. Sec23a is one of the component of the COPII vesicles coat and its GTPase activating function on Sar1 is one of the key mechanisms of COPII assembly. Interestingly, we found that ER Stress reduces the association to the ER membrane of Sec23a. Concomitantly, FRAP and FLIP analysis of Sec23a revealed that ER stress accelerates its recycling kinetics on ER membrane. The reduced permanence of Sec23a at the ERES could be the mean through which ER Stress modulates COPII assembling and vesicular trafficking. Moreover, we found that Sec23a is mono-ubiquitinated in mammalian cells in two different sites of its second β-barrel domainand that the induction of ER stress reduces the amount of mono-ubiquitinated Sec23a. Noteworthy, this modification is a mono-ubiquitination on two different cysteines of the β-Barrel domain that is implicated in the binding of Sec23a to the ER membrane. Emerging evidences have demonstrated that ubiquitination on cysteines is implicated in many processes including signal transduction and membrane translocation. The regulatory function of cysteine ubiquitination, its localization in the β-Barrel domain and its impairment during ER stress strictly support the idea that Sec23a is the moleculartarget of ER Stress-dependent modulation of vesicular trafficking and that the regulation of Sec23a ubiquitination is the molecular mechanism involved in this phenomena.

Sec23a as the key molecular target of ER Stress dependent modulation of COPII assembling G. Amodio1, O. Moltedo1, V. Pecoraro1, P. Remondelli2 1Dipartimento di Farmacia, Univ. of Salerno, Italy 2Dipartimento di Medicina e Chirurgia , Univ. of Salerno, Italy

AMODIO, GIUSEPPINA;MOLTEDO, Ornella;REMONDELLI, PAOLO
2013

Abstract

Exit from the Endoplasmic Reticulum (ER) of newly synthesized proteins is mediated by COPII vesicles that bud from the ER at the ER Exit Sites (ERESs). Disruption of ER homeostasis causes accumulation of unfolded and misfolded proteins in the ER. This condition is referred as ER stress. Several evidences suggest a link between the ER stress and the vesicular trafficking within of the early secretory pathway. Previously, we demonstrated that ER Stress rapidly impairs the anterograde transport to the Golgi complex and the formation of COPII vesicles. Sec23a is one of the component of the COPII vesicles coat and its GTPase activating function on Sar1 is one of the key mechanisms of COPII assembly. Interestingly, we found that ER Stress reduces the association to the ER membrane of Sec23a. Concomitantly, FRAP and FLIP analysis of Sec23a revealed that ER stress accelerates its recycling kinetics on ER membrane. The reduced permanence of Sec23a at the ERES could be the mean through which ER Stress modulates COPII assembling and vesicular trafficking. Moreover, we found that Sec23a is mono-ubiquitinated in mammalian cells in two different sites of its second β-barrel domainand that the induction of ER stress reduces the amount of mono-ubiquitinated Sec23a. Noteworthy, this modification is a mono-ubiquitination on two different cysteines of the β-Barrel domain that is implicated in the binding of Sec23a to the ER membrane. Emerging evidences have demonstrated that ubiquitination on cysteines is implicated in many processes including signal transduction and membrane translocation. The regulatory function of cysteine ubiquitination, its localization in the β-Barrel domain and its impairment during ER stress strictly support the idea that Sec23a is the moleculartarget of ER Stress-dependent modulation of vesicular trafficking and that the regulation of Sec23a ubiquitination is the molecular mechanism involved in this phenomena.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11386/4653085
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