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

Abstract

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.

ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

“…In addition, these transducers sense lipid bilayer stress (LBS) independently of the accumulation of misfolded protein in the ER lumen [2,[8][9][10][11][12]. First identified as the sole ER stress transducer in S. cerevisiae, Ire1 is essential for cell viability during ER stress [13].…”

ER p18 regulates activation of ATF 6α during unfolded protein response

“…For trafficking to occur, proteins involved in retention dissociate, disulfides within the lumenal domain are reduced, ATF6α oligomers dissociate, and reduced monomeric ATF6α is packaged into COPII‐coated vesicles for transport out of the ER (Fig ; Nadanaka et al , ; Schindler & Schekman, ). The initial trigger for release comes from either unfolded proteins (Ye et al , ) or alterations to the lipid composition of the ER membrane (Tam et al , ). BiP is known to dissociate from ATF6α in the presence of unfolded proteins (Shen et al , ), which could potentially lead to the trafficking of disulfide‐bonded ATF6α to the Golgi.…”

Type I interferons and endoplasmic reticulum stress in health and disease

“…PERK commands a slightly different pathway for this purpose, it enforces translational inhibition of IκB thereby freeing NF-κB for engaging its transcriptional program (Blais et al, 2006;Halliday et al, 2017;Pytel et al, 2016;Qiao et al, 2017;Tam et al, 2012). Lastly, although ATF6 axis has been shown to influence NF-κB activation yet, the exact mechanism underlying this cascade has not been established (Tam et al, 2018;Yamazaki et al, 2009). Similar to NF-κB, AP1 is an important inflammatory transcription factor composed of monomers of a variety of proteins, like Jun proto-oncogene or JUN, Fos proto-oncogene or FOS, ATF and/or, musculoaponeurotic fibrosarcoma (MAF) (Uluçkan et al, 2015;van Dam and Castellazzi, 2001;Wagner, 2010).…”

“…On the other hand, activated IRE1 also displays some degree of kinase activity, which it exploits for trans-autophosphorylation; although the exact identity of other downstream substrates targeted for phosphorylation by IRE1 remains enigmatic (Ali et al, 2011;Feldman and Maly, 2017;Korennykh et al, 2009;Lee et al, 2008;Prischi et al, 2014). In comparison to PERK and IRE1, ATF6 activation mechanism is highly distinct in the UPR setting ( Jerry Chiang and Lin, 2014;Sundaram et al, 2018;Tam et al, 2018;Teske et al, 2011;Yoshida et al, 2001). The titration of GRP78 away from ATF6 encourages its transportation toward the Golgi complex wherein it is sliced by particular Golgi-resident proteases (Fig.…”