Herp depletion protects from protein aggregation by up-regulating autophagy
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- 作者：Clara Quiroga ; Damian Gatica ; Felipe Paredes ; Roberto Bravo ; Rodrigo Troncoso ; Zully Pedrozo ; Andrea E. Rodriguez ; Barbra Toro ; Mario Chiong ; Jose Miguel Vicencio ; Claudio Hetz ; Sergio Lav ; ero
- 关键词：Poly-ubiquitinated protein ; Endoplasmic reticulum stress ; Autophagy ; UPR ; Protein aggregation ; Beclin-1
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：December, 2013
- 年：2013
- 卷：1833
- 期：12
- 页码：3295-3305
- 全文大小：1246 K
文摘
Herp is an endoplasmic reticulum (ER) stress inducible protein that participates in the ER-associated protein degradation (ERAD) pathway. However, the contribution of Herp to other protein degradation pathways like autophagy and its connection to other types of stress responses remain unknown. Here we report that Herp regulates autophagy to clear poly-ubiquitin (poly-Ub) protein aggregates. Proteasome inhibition and glucose starvation (GS) led to a high level of poly-Ub protein aggregation that was drastically reduced by stably knocking down Herp (shHerp cells). The enhanced removal of poly-Ub inclusions protected cells from death caused by glucose starvation. Under basal conditions and increasingly after stress, higher LC3-II levels and GFP-LC3 puncta were observed in shHerp cells compared to control cells. Herp knockout cells displayed basal up-regulation of two essential autophagy regulators鈥擜tg5 and Beclin-1, leading to increased autophagic flux. Beclin-1 up-regulation was due to a reduction in Hrd1 dependent proteasomal degradation, and not at transcriptional level. The consequent higher autophagic flux was necessary for the clearance of aggregates and for cell survival. We conclude that Herp operates as a relevant factor in the defense against glucose starvation by modulating autophagy levels. These data may have important implications due to the known up-regulation of Herp in pathological states such as brain and heart ischemia, both conditions associated to acute nutritional stress.