Endoplasmic Reticulum Stress Triggers Autophagy<sup><a href="#FN1" rid="FN1" class=" fn">*</a></sup>

From the Life Sciences Institute and Departments of Molecular, Cellular, and Developmental Biology and Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109

^{To whom correspondence should be addressed: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216. Tel.: 734-615-6556; Fax: 734-763-6492; E-mail:}ude.hcimu@yksnoilk.

Abstract

Eukaryotic cells have evolved strategies to respond to stress conditions. For example, autophagy in yeast is primarily a response to the stress of nutrient limitation. Autophagy is a catabolic process for the degradation and recycling of cytosolic, long lived, or aggregated proteins and excess or defective organelles. In this study, we demonstrate a new pathway for the induction of autophagy. In the endoplasmic reticulum (ER), accumulation of misfolded proteins causes stress and activates the unfolded protein response to induce the expression of chaperones and proteins involved in the recovery process. ER stress stimulated the assembly of the pre-autophagosomal structure. In addition, autophagosome formation and transport to the vacuole were stimulated in an Atg protein-dependent manner. Finally, Atg1 kinase activity reflects both the nutritional status and autophagic state of the cell; starvation-induced autophagy results in increased Atg1 kinase activity. We found that Atg1 had high kinase activity during ER stress-induced autophagy. Together, these results indicate that ER stress can induce an autophagic response.

Abstract

Footnotes

^{This work was supported by National Institutes of Health Public Health Service Grant GM53396 (to D. J. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “}advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^{The abbreviations used are:}

Cvt: cytoplasm to vacuole targeting
Atg8-PE: Atg8 conjugated to phosphatidylethanolamine
CCCP: carbonyl cyanide m-chlorophenylhydrazone
ER: endoplasmic reticulum
ERAD: ER-associated degradation
PAS: pre-autophagosomal structure
TM: tunicamycin
UPR: unfolded protein response
prApe1: precursor Ape1
GFP: green fluorescent protein.

^{T. Yorimitsu, U. Nair, Z. Yang, and D. J. Klionsky, unpublished data.}

Footnotes

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