HRES-1-Rab4 Promotes the Formation of LC3 Autophagosomes and the Accumulation of Mitochondria during AutophagyReport as inadecuate




HRES-1-Rab4 Promotes the Formation of LC3 Autophagosomes and the Accumulation of Mitochondria during Autophagy - Download this document for free, or read online. Document in PDF available to download.

HRES-1-Rab4 is a small GTPase that regulates endocytic recycling. It has been colocalized to mitochondria and the mechanistic target of rapamycin mTOR, a suppressor of autophagy. Since the autophagosomal membrane component microtubule-associated protein light chain 3 LC3 is derived from mitochondria, we investigated the impact of HRES-1-Rab4 on the formation of LC3+ autophagosomes, their colocalization with HRES-1-Rab4 and mitochondria, and the retention of mitochondria during autophagy induced by starvation and rapamycin. HRES-1-Rab4 exhibited minimal baseline colocalization with LC3, which was enhanced 22-fold upon starvation or 6-fold upon rapamycin treatment. Colocalization of HRES-1-Rab4 with mitochondria was increased >2-fold by starvation or rapamycin. HRES-1-Rab4 overexpression promoted the colocalization of mitochondria with LC3 upon starvation or rapamycin treatment. A dominant-negative mutant, HRES-1-Rab4S27N had reduced colocalization with LC3 and mitochondria upon starvation but not rapamycin treatment. A constitutively active mutant, HRES-1-Rab4Q72L showed diminished colocalization with LC3 but promoted the partitioning of mitochondria with LC3 upon starvation or rapamycin treatment. Phosphorylation-resistant mutant HRES-1-Rab4S204Q showed diminished colocalization with LC3 but increased partitioning to mitochondria. A newly discovered C-terminally truncated native isoform, HRES-1-Rab41–121, showed enhanced localization to LC3 and mitochondria without starvation or rapamycin treatment. HRES-1-Rab41–121 increased the formation of LC3+ autophagosomes in resting cells, while other isoforms promoted autophagosome formation upon starvation. HRES-1-Rab4, HRES-1-Rab41–121, HRES-1-Rab4Q72L and HRES-1-Rab4S204Q promoted the accumulation of mitochondria during starvation. The specificity of HRES-1-Rab4-mediated mitochondrial accumulation is indicated by its abrogation by dominant-negative HRES-1-Rab4S27N mutation. The formation of interconnected mitochondrial tubular networks was markedly enhanced by HRES-1-Rab4Q72L upon starvation, which may contribute to the retention of mitochondria during autophagy. The present study thus indicates that HRES-1-Rab4 regulates autophagy through promoting the formation of LC3+ autophagosomes and the preservation of mitochondria.



Author: Gergely Talaber, Gabriella Miklossy, Zachary Oaks, Yuxin Liu, Sharon A. Tooze, Dmitriy M. Chudakov, Katalin Banki, Andras Perl

Source: http://plos.srce.hr/



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