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Influx of acetyl‐CoA into the ER lumen regulates the induction of autophagy during the UPR
Author(s) -
Puglielli Luigi,
Pehar Mariana
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.953.1
Subject(s) - unfolded protein response , autophagy , microbiology and biotechnology , acetylation , programmed cell death , endoplasmic reticulum , endoplasmic reticulum associated protein degradation , chemistry , lysine , vacuole , mutant , biology , apoptosis , biochemistry , cytoplasm , gene , amino acid
One of the main functions of the UPR is to ensure disposal of large protein aggregates that accumulate in the lumen of the ER while avoiding, under non‐lethal levels of ER stress, cell death. When tightly controlled, ERAD(II) allows the cell to recover from the transient accumulation of protein aggregates; however, when unchecked it can be detrimental and cause autophagic/type 2 cell death. Here we report the results of a proteomic study showing that a large number of ER‐resident and ‐transiting proteins undergoes Nε‐lysine acetylation in the lumen of the organelle. The list of ER‐resident proteins includes chaperones and enzymes involved with post‐translational modification and folding. We also show that during ER stress IRE1/XBP1 controls the influx of acetyl‐CoA into the lumen of the ER by inducing the ER membrane acetyl‐CoA transporter SLC33A1/AT‐1. Failure to induce AT‐1 and maintain the acetylation status of the ER leads to widespread autophagic cell death. Mechanistically, the regulation of the autophagic process involves Nε‐lysine acetylation of Atg9A. In fact, a gain‐of‐acetylation mutant form of Atg9A protected from autophagic cell death while a loss‐of‐acetylation mutant achieved the opposite effect. Finally, we report that a mutant form of AT‐1 that is associated with Autosomal Dominant Spastic Paraplegia is unable to form homodimers and transport acetyl‐CoA across the membrane. Supported by NIH