title: Non-targeting siRNA induces NPGPx expression to cooperate with exoribonuclease XRN2 for releasing the stress.
abstract: Short interfering RNAs (siRNAs) target specific mRNAs for their degradation mediated by RNA-induced silencing complex (RISC). Persistent activation of siRNA-RISC frequently leads to non-targeting toxicity. However, how cells mediate this stress remains elusive. In this communication, we found that the presence of non-targeting siRNA selectively induced the expression of an endoplasmic reticulum (ER)-resident protein, non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), but not other ER-stress proteins including GRP78, Calnexin and XBP1. Cells suffering from constant non-targeting siRNA stress grew slower and prolonged G1 phase, while NPGPx-depleted cells accumulated mature non-targeting siRNA and underwent apoptosis. Upon the stress, NPGPx covalently bound to exoribonuclease XRN2, facilitating XRN2 to remove accumulated non-targeting siRNA. These results suggest that NPGPx serves as a novel responder to non-targeting siRNA-induced stress in facilitating XRN2 to release the non-targeting siRNA accumulation.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors: Pei-Chi
authors: PC
authors: Wei
authors: Wen-Ting
authors: WT
authors: Lo
authors: Mei-I
authors: MI
authors: Su
authors: Jin-Yuh
authors: JY
authors: Shew
authors: Wen-Hwa
authors: WH
authors: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D000091342:Endoplasmic Reticulum Chaperone BiP; D005095:Exoribonucleases / Q000378:metabolism* / Q000502:physiology; D016193:G1 Phase; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010544:Peroxidases / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D010544:Peroxidases; C558641:GPX7 protein, human; D005979:Glutathione Peroxidase; D005095:Exoribonucleases; C092452:Xrn2 protein, mouse; C120903:XRN2 protein, human