SLC33A1/AT-1 protein regulates the induction of autophagy downstream of IRE1/XBP1 pathway.
One of the main functions of the unfolded protein response is to ensure disposal of large protein aggregates that accumulate in the lumen of the endoplasmic reticulum (ER) whereas avoiding, at least under nonlethal levels of ER stress, cell death. When tightly controlled, autophagy-dependent ER-associated degradation (ERAD(II)) allows the cell to recover from the transient accumulation of protein aggregates; however, when unchecked, it can be detrimental and cause autophagic cell death/type 2 cell death. Here we show that IRE1/XBP1 controls the induction of autophagy/ERAD(II) during the unfolded protein response by activating the ER membrane transporter SLC33A1/AT-1, which ensures continuous supply of acetyl-CoA into the lumen of the ER. Failure to induce AT-1 leads to widespread autophagic cell death. Mechanistically, the regulation of the autophagic process involves N(ε)-lysine acetylation of Atg9A.
Department of Medicine, University of Wisconsin, Madison, WI 53705, USA.
Mariana
M
Pehar
Mary Cabell
MC
Jonas
Theresa M
TM
Hare
Luigi
L
Puglielli
D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins; D000071717:X-Box Binding Protein 1
C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D000071701:Regulatory Factor X Transcription Factors; C484549:SLC33A1 protein, human; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D000105:Acetyl Coenzyme A; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases