ATF6α induces XBP1-independent expansion of the endoplasmic reticulum

Bommiasamy, Hemamalini; Back, Sung Hoon; Fagone, Paolo; Lee, Kyung-Ho; Meshinchi, Sasha; Vink, Elizabeth I.; Sriburi, Rungtawan; Frank, Matthew W.; Jackowski, Suzanne; Kaufman, Randal J.; Brewer, Joseph W.

doi:10.1242/jcs.045625

Cited by 243 publications

(212 citation statements)

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“…Several studies have demonstrated that forced expression of cleaved ATF6α is alone sufficient to up-regulate ER chaperones (4,20,22); hence, an increase in classic UPR targets might have been expected also under our condition. It is, however, well known that ATF6α dimerizes with other transcription factors that modulate its activity (23)(24)(25).…”

Section: Discussionmentioning

confidence: 80%

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

Maiuolo

Bulotta

Verderio

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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It is well known that the endoplasmic reticulum (ER) is capable of expanding its surface area in response both to cargo load and to increased expression of resident membrane proteins. Although the response to increased cargo load, known as the unfolded protein response (UPR), is well characterized, the mechanism of the response to membrane protein load has been unclear. As a model system to investigate this phenomenon, we have used a HeLa-TetOff cell line inducibly expressing a tail-anchored construct consisting of an Nterminal cytosolic GFP moiety anchored to the ER membrane by the tail of cytochrome b5 [GFP-b(5)tail]. After removal of doxycycline, GFP-b(5)tail is expressed at moderate levels (1-2% of total ER protein) that, nevertheless, induce ER proliferation, as assessed both by EM and by a three-to fourfold increase in phosphatidylcholine synthesis. We investigated possible participation of each of the three arms of the UPR and found that only the activating transcription factor 6 (ATF6) arm was selectively activated after induction of GFPb(5)tail expression; peak ATF6α activation preceded the increase in phosphatidylcholine synthesis. Surprisingly, up-regulation of known ATF6 target genes was not observed under these conditions. Silencing of ATF6α abolished the ER proliferation response, whereas knockdown of Ire1 was without effect. Because GFP-b(5)tail lacks a luminal domain, the response we observe is unlikely to originate from the ER lumen. Instead, we propose that a sensing mechanism operates within the lipid bilayer to trigger the selective activation of ATF6.phospholipid biosynthesis | tail-anchored proteins | membrane biogenesis C ells are capable of adjusting the dimensions, architecture, and molecular composition of their organelles to changing functional needs. The endoplasmic reticulum (ER) offers a well-studied example of such organelle plasticity. When exposed to altered conditions, it initiates signaling cascades that result in the adjustment of its size and composition to the new situation. Among these signaling pathways, the one triggered by increased demand on the lumenal folding machinery, known as the unfolded protein response (UPR), plays a prominent role and has been extensively investigated (1).In yeast, the UPR is mediated by the ER transmembrane kinase/ endonuclease Ire1p, whereas in mammalian cells, the pathway has evolved to a higher degree of complexity, with the participation of two additional transmembrane sensors: the basic leucine zipper (bZIP) transcriptional regulator activating transcription factor 6α/ β (ATF6α/β) and the PKR-like ER kinase (PERK) (1). In the presence of unfolded proteins in the ER lumen, the three sensors induce changes in the activity of the transcriptional and translational apparatus that alleviate ER stress by (i) increasing the capacity of the lumenal folding machinery; (ii) enhancing ER-associated degradation; (iii) diminishing delivery of newly synthesized proteins to the ER lumen; and (iv) increasing phospholipid synthesis, with a resulting expans...

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Section: Discussionmentioning

confidence: 80%

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

Maiuolo

Bulotta

Verderio

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The three branches of the UPR exhibit extensive overlap in both their downstream targets and in the transcriptional networks that become activated in response to ER stress (43)(44)(45)(46). Although previous studies have linked the UPR to MIST1 activity (19,24,47), the extensive cross talk and overlap between distinct UPR branches has complicated identifying which UPR branch specifically leads to induction of MIST1.…”

Section: Resultsmentioning

confidence: 99%

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Hess

Strelau

Karki

et al. 2016

Molecular and Cellular Biology

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Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

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“…The detrimental effects of UPR activation in the lens were probably mediated by both activation of UPR-specific transcription factors and UPR-induced global translational attenuation. The production of ATF6(N) and XBP1(S) could alter fiber cell transcriptional programs by up-regulating genes involved in ER folding and ER biogenesis in lens fiber cells that would normally undergo programmed degradation of nuclei and cytoplasmic organelles (59,62,88). On the other hand, PERK-mediated translational attenuation could interfere with lens fiber cell differentiation through lowering the synthesis of crystallins and other fiber cell-specific proteins that are needed for fiber cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

Firtina

Danysh

Bai

et al. 2009

Journal of Biological Chemistry

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Human diseases caused by mutations in extracellular matrix genes are often associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown. Using two different mouse models, we show that the accumulation of collagen chains in the secretory pathway activates the stress signaling pathway termed unfolded protein response (UPR). Transgenic mice expressing ectopic Col4a3 and Col4a4 genes in the lens exhibited activation of IRE1, ATF6, and PERK associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1 ؉/⌬ex40 mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses, suggesting that low levels of UPR activation are not proapoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.The ocular lens is a transparent, cellular structure that refracts light onto the retina, resulting in high resolution vision. Many environmental risk factors and single gene defects are known or hypothesized to result in clouding of the lens, a condition known as cataract. Cataract is the primary cause of blindness worldwide (1, 2), with autosomal dominant congenital cataract being the leading cause of treatable childhood blindness (3, 4). Cataract surgery is the most commonly performed surgical operation in the United States and consumes 60% of the Medicare budget for vision (5, 6).Cataract can be a multifactorial disease and is often associated with systemic or genetic disorders, such as diabetes and Lowe syndrome (7-9). Notably, human diseases caused by mutations in extracellular matrix (ECM) 4 genes are also often associated with an increased risk of cataract. Stickler and Marshall syndromes are two disorders caused by mutations in the COL2A1 gene that are associated with the early onset of distinctive cataracts (10, 11). Alport syndrome, caused by mutations in either the COL4A3, COL4A4, or COL4A5 genes, is also associated with lens capsule abnormalities and cataract formation (12)(13)(14). Humans carrying mutations in the COL4A1 locus often exhibit lens abnormalities and cataracts along with porencephaly and sporadic intracerebral hemorrhage (15-19). To date, approximately 13 independent mutations in the mouse Col4a1 locus and three independent mutations in mouse Col4a2 locus have been found to cause vacuolar cataract and lens abnormalities in mice (19 -21). However, the underlying mechanisms of cataract pathogenesis resulting from these collagen mutations are still unknown.In other tissues, mutations in genes encoding secretory pathway proteins have been found to cause endoplasmic reticulum (ER) stress and...

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ATF6α induces XBP1-independent expansion of the endoplasmic reticulum

Cited by 243 publications

References 50 publications

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

Selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

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