ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

Ye J, Rawson RB, Komuro R, Chen X, Davé UP, Prywes R, Brown MS, Goldstein JL
Mol Cell. 2000 6 (6): 1355-64

PMID: 11163209 · DOI:10.1016/s1097-2765(00)00133-7

ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.

MeSH Terms (30)

Activating Transcription Factor 6 Amino Acid Motifs Amino Acid Sequence Animals Carrier Proteins CCAAT-Enhancer-Binding Proteins Cell Line DNA-Binding Proteins Endopeptidases Endoplasmic Reticulum Heat-Shock Proteins Humans Immunoblotting Intracellular Membranes Intracellular Signaling Peptides and Proteins Membrane Proteins Molecular Chaperones Molecular Sequence Data Mutation Proprotein Convertases Protein Binding Protein Processing, Post-Translational RNA, Messenger Sequence Alignment Serine Endopeptidases Sterol Regulatory Element Binding Protein 1 Thapsigargin Transcription, Genetic Transcription Factors Tunicamycin

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