title: AT-1 is the ER membrane acetyl-CoA transporter and is essential for cell viability.
abstract: The transient or permanent modification of nascent proteins in the early secretory pathway is an essential cellular function that ensures correct folding and maturation of membrane and secreted proteins. We have recently described a new form of post-translational regulation of the membrane protein β-site APP cleaving enzyme 1 (BACE1) involving transient lysine acetylation in the lumen of the endoplasmic reticulum (ER). The essential components of this process are two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 and ATase2, and a membrane transporter that translocates acetyl-CoA into the lumen of the ER. Here, we report the functional identification of acetyl-CoA transporter 1 (AT-1) as the ER membrane acetyl-CoA transporter. We show that AT-1 regulates the acetylation status of ER-transiting proteins, including the membrane proteins BACE1, low-density lipoprotein receptor and amyloid precursor protein (APP). Finally, we show that AT-1 is essential for cell viability as its downregulation results in widespread cell death and induction of features characteristic of autophagy.
authors.affiliation: Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Mary Cabell
authors.initials: MC
authors.lastname: Jonas
authors.forename: Mariana
authors.initials: M
authors.lastname: Pehar
authors.forename: Luigi
authors.initials: L
authors.lastname: Puglielli
mesh_terms: D000107:Acetylation; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D055571:Secretory Pathway / Q000235:genetics; D019076:Transgenes / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D026901:Membrane Transport Proteins; D034741:RNA, Small Interfering; C105440:Slc33a1 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
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