Authors: Isamu Sakabe Rong Hu Lu Jin Robert Clarke Usha N Kasid
Publish Date: 2015/08/13
Volume: 153, Issue: 2, Pages: 285-297
Abstract
Endoplasmic reticulum ER stress leads to activation of the unfolded protein response UPR signaling cascade and induction of an apoptotic cell death autophagy oncogenesis metastasis and/or resistance to cancer therapies Mechanisms underlying regulation of ER transmembrane proteins PERK IRE1α and ATF6α/β and how the balance of these activities determines outcome of the activated UPR remain largely unclear Here we report a novel molecule transmembrane protein 33 TMEM33 and its actions in UPR signaling Immunoblotting and northern blot hybridization assays were used to determine the effects of ER stress on TMEM33 expression levels in various cell lines Transient transfections immunofluorescence subcellular fractionation immunoprecipitation and immunoblotting were used to study the subcellular localization of TMEM33 the binding partners of TMEM33 and the expression of downstream effectors of PERK and IRE1α Our data demonstrate that TMEM33 is a unique ER stressinducible and ER transmembrane molecule and a new binding partner of PERK Exogenous expression of TMEM33 led to increased expression of peIF2α and pIRE1α and their known downstream effectors ATF4CHOP and XBP1S respectively in breast cancer cells TMEM33 overexpression also correlated with increased expression of apoptotic signals including cleaved caspase7 and cleaved PARP and an autophagosome protein LC3II and reduced expression of the autophagy marker p62 TMEM33 is a novel regulator of the PERKeIE2αATF4 and IRE1XBP1 axes of the UPR signaling Therefore TMEM33 may function as a determinant of the ER stressresponsive events in cancer cells
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