The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

• Published in: Developmental cell Vol. 46; no. 3; pp. 327 - 343.e7
• Main Authors: Tam, Arvin B., Roberts, Lindsay S., Chandra, Vivek, Rivera, Io Guane, Nomura, Daniel K., Forbes, Douglass J., Niwa, Maho
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2018
• Subjects: Activating Transcription Factor 6 - drug effects; Activating Transcription Factor 6 - metabolism; ATF6; Cell Line; dihydroceramide; dihydrosphingosine; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - drug effects; Fenretinide - pharmacology; Humans; lipotoxic stress; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - metabolism; proteotoxic stress; sphingolipids; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; transcription upregulation; Transcription, Genetic - drug effects; transmembrane domain; unfolded protein response; Unfolded Protein Response - genetics; unfolded protein response; dihydrosphingosine; lipotoxic stress; sphingolipids; transmembrane domain; proteotoxic stress; dihydroceramide; ER; ATF6; transcription upregulation
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2018.04.023

The unfolded protein response (UPR) is induced by proteotoxic stress of the endoplasmic reticulum (ER). Here we report that ATF6, a major mammalian UPR sensor, is also activated by specific sphingolipids, dihydrosphingosine (DHS) and dihydroceramide (DHC). Single mutations in a previously undefined transmembrane domain motif that we identify in ATF6 incapacitate DHS/DHC activation while still allowing proteotoxic stress activation via the luminal domain. ATF6 thus possesses two activation mechanisms: DHS/DHC activation and proteotoxic stress activation. Reporters constructed to monitor each mechanism show that phenobarbital-induced ER membrane expansion depends on transmembrane domain-induced ATF6. DHS/DHC addition preferentially induces transcription of ATF6 target lipid biosynthetic and metabolic genes over target ER chaperone genes. Importantly, ATF6 containing a luminal achromatopsia eye disease mutation, unresponsive to proteotoxic stress, can be activated by fenretinide, a drug that upregulates DHC, suggesting a potential therapy for this and other ATF6-related diseases including heart disease and stroke. [Display omitted] •ATF6 is activated not only by proteotoxic stress but also by the sphingolipids DHS and DHC•Proteotoxic stress and sphingolipids activate ATF6 via separate domains•Mutations in a transmembrane motif in ATF6 block sphingolipid but not proteotoxic activation•Sphingolipids DHS and DHC upregulate ER lipid biosynthetic genes over chaperone genes The unfolded protein response (UPR), often perturbed by proteotoxic stress or disease, also responds to lipotoxic stress. Tam et al. find that dihydrosphingosine and dihydroceramide, early sphingolipid intermediates, directly activate the mammalian UPR sensor ATF6, via a domain distinct from that targeted by proteotoxic stress, and preferentially activate lipid biosynthetic genes.