scholarly journals A Role for SIR-2.1 Regulation of ER Stress Response Genes in Determining C. elegans Life Span

2005 ◽  
Vol 9 (5) ◽  
pp. 605-615 ◽  
Author(s):  
Mohan Viswanathan ◽  
Stuart K. Kim ◽  
Ala Berdichevsky ◽  
Leonard Guarente
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Life Span ◽  
C Elegans ◽  
Er Stress Response ◽  
Stress Response Genes

scholarly journals Conserved Roles of C. elegans and Human MANFs in Sulfatide Binding and Cytoprotection

2018 ◽  
Author(s):  
Meirong Bai ◽  
Roman Vozdek ◽  
Aleš Hnízda ◽  
Chenxiao Jiang ◽  
Bingying Wang ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Dopamine Neurons ◽  
Lipid Mediator ◽  
Outer Cell ◽  
Dependent Manner ◽  
C Elegans ◽  
Er Stress Response

AbstractMesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protect dopamine neurons and cardiomyocytes from ER stress and apoptosis. The mechanism of action of extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal ER stress response, we identified the gene Y54G2A.23 as the evolutionarily conserved C. elegans MANF orthologue. We find that MANF binds to the lipid sulfatide, also known as 3-O-sulfogalactosylceramide present in serum and outer-cell membrane leaflets, directly in isolated forms and in reconstituted lipid micelles. Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. Heightened ER stress responses of MANF-null C. elegans mutants and mammalian cells are alleviated by human MANF in a sulfatide-dependent manner. Our results demonstrate conserved roles of MANF in sulfatide binding and ER stress response, supporting sulfatide as a long-sought lipid mediator of MANF’s cytoprotection.

scholarly journals Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking

2020 ◽  
Vol 6 (7) ◽  
pp. eaay7667 ◽  
Author(s):  
Zhe Zhang ◽  
Meirong Bai ◽  
Guilherme Oliveira Barbosa ◽  
Andrew Chen ◽  
Yuehua Wei ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Rna Interference ◽  
Caenorhabditis Elegans ◽  
Stress Response ◽  
Er Stress ◽  
C Elegans ◽  
Er Stress Response ◽  
Evolutionarily Conserved ◽  
Human Disorders ◽  
Intracellular Collagen

Collagen is the most abundant protein in animals. Its dysregulation contributes to aging and many human disorders, including pathological tissue fibrosis in major organs. How premature collagen proteins in the endoplasmic reticulum (ER) assemble and route for secretion remains molecularly undefined. From an RNA interference screen, we identified an uncharacterized Caenorhabditis elegans gene tmem-131, deficiency of which impairs collagen production and activates ER stress response. We find that amino termini of human TMEM131 contain bacterial PapD chaperone–like domains, which recruit premature collagen monomers for proper assembly and secretion. Carboxy termini of TMEM131 interact with TRAPPC8, a component of the TRAPP tethering complex, to drive collagen cargo trafficking from ER to the Golgi. We provide evidence that previously undescribed roles of TMEM131 in collagen recruitment and secretion are evolutionarily conserved in C. elegans, Drosophila, and humans.

scholarly journals The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans

2013 ◽  
Vol 126 (18) ◽  
pp. 4136-4146 ◽  
Author(s):  
M. Safra ◽  
S. Ben-Hamo ◽  
C. Kenyon ◽  
S. Henis-Korenblit
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Protein Metabolism ◽  
Secretory Protein ◽  
C Elegans ◽  
Er Stress Response ◽  
Stress Response Pathway

scholarly journals The conserved ER-transmembrane protein TMEM39 coordinates with COPII to promote collagen secretion and prevent ER stress

2020 ◽  
Author(s):  
Zhe Zhang ◽  
Shuo Luo ◽  
Guilherme Oliveira Barbosa ◽  
Meirong Bai ◽  
Thomas B. Kornberg ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Fat Body ◽  
Transmembrane Protein ◽  
Vesicular Trafficking ◽  
Collagen Production ◽  
C Elegans ◽  
Er Stress Response ◽  
Collagen Secretion ◽  
Evolutionarily Conserved

AbstractDysregulation of collagen production and secretion contributes to aging and tissue fibrosis of major organs. How premature collagen proteins in the endoplasmic reticulum (ER) route as specialized cargos for secretion remains to be fully elucidated. Here, we report that TMEM39, an ER-localized transmembrane protein, regulates production and secretory cargo trafficking of procollagen. We identify the C. elegans ortholog TMEM-39 from an unbiased RNAi screen and show that deficiency of tmem-39 leads to striking defects in cuticle collagen production and constitutively high ER stress response. RNAi knockdown of the tmem-39 ortholog in Drosophila causes similar defects in collagen secretion from fat body cells. The cytosolic domain of human TMEM39A binds to Sec23A, a vesicle coat protein that drives collagen secretion and vesicular trafficking. TMEM-39 regulation of collagen secretion is independent of ER stress response and autophagy. We propose that roles of TMEM-39 in collagen secretion and preventing ER stress are likely evolutionarily conserved.

Single nucleotide polymorphisms (SNPs) in endoplasmic reticulum (ER) stress response genes to predict first-line treatment outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from the MAVERICC and FIRE-3 trials.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 103-103
Author(s):  
Francesca Battaglin ◽  
Hiroyuki Arai ◽  
Joshua Millstein ◽  
Sebastian Stintzing ◽  
Aparna Raj Parikh ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Treatment Outcome ◽  
Stress Response ◽  
Er Stress ◽  
P Value ◽  
Line Treatment ◽  
First Line ◽  
Er Stress Response ◽  
Stress Response Genes ◽  
First Line Treatment

103 Background: ER stress, triggered by the disruption of intracellular protein homeostasis, promotes the activation of a highly conserved adaptive program called unfolded protein response (UPR). UPR signaling has been reported to contribute to tumor initiation and progression, as well as microenvironment remodeling and chemoresistance in multiple cancer types, including CRC. Several studies point to a direct role of the UPR in tumor angiogenesis and an interaction with EGFR signaling. We therefore hypothesized that genetic variants in ER stress response genes may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 17 functional SNPs in 8 core genes of the ER stress response pathway ( IRE1, PERK, ATF6, XBP1, CHOP, GRP78, GADD34, ATF4) was analyzed on a total of 560 pts enrolled in two independent randomized first-line trials: MAVERICC (FOLFIRI/bevacizumab, [bev] n = 163; FOLFOX6/bev, n = 161), and FIRE-3 (FOLFIRI/bev, n = 107; FOLFIRI/cetuximab [cet], n = 129). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. The association between SNPs and clinical outcomes was evaluated using Cox regression and log-rank tests. The SNP*treatment interaction was assessed in both trials. Results: IRE1 rs16947383 any T allele variant was associated with shorter progression free survival (PFS) and overall survival (OS) compared to the C/C genotype in pts treated with FOLFIRI/bev in the MAVERICC trial both in uni- and multivariate analysis: 10.5 vs 14.1 months for PFS, adjusted hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.12-2.99, adjusted P-value = 0.02; 23.8 vs 38.4 months for OS, adjusted HR 2.12, 95%CI 1.1-4.09, adjusted P-value = 0.02. The association with OS was validated in the FIRE-3 FOLFIRI/bev arm where any T allele carriers showed significantly shorter OS compared to the C/C genotype in both uni- and multivariate analysis: 21.1 vs 44.2 months, adjusted HR 2.06, 95%CI 1.01-4.18, adjusted P-value = 0.05. This effect was not observed in MAVERICC FOLFOX6 and FIRE-3 cet cohorts. A significant interaction was found between IRE1 rs16947383 and treatment on OS in both trials: P = 0.04 in MAVERICC (FOLFIRI vs FOLFOX6), and P = 0.03 in FIRE-3 (bev vs cet). In the MAVERICC FOLFOX6/bev arm, XBP1 rs2239815 and PERK rs6731022 SNPs were associated with shorter PFS and OS, while GADD34 rs610308 with longer OS, in multivariable analysis ( P < 0.05). Conclusions: Our results provide evidence that germline polymorphisms in ER stress response genes may have a predictive value in mCRC pts receiving first-line bev-based treatment and contribute to modulate anti-VEGF efficacy.

scholarly journals Broadly Conserved TMEM-131 Family Proteins in Collagen Production and Secretory Cargo Trafficking

2019 ◽  
Author(s):  
Zhe Zhang ◽  
Meirong Bai ◽  
Guilherme Oliveira Barbosa ◽  
Andrew Chen ◽  
Yuehua Wei ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Rnai Screen ◽  
Collagen Production ◽  
Abundant Protein ◽  
C Elegans ◽  
Er Stress Response ◽  
Evolutionarily Conserved ◽  
Human Disorders

AbstractCollagen is the most abundant protein in animals. Its dysregulation contributes to ageing and human disorders including tissue fibrosis in major organs. How premature collagens in the endoplasmic reticulum (ER) assemble and route for secretion remains molecularly undefined. From an RNAi screen, we identified an uncharacterized C. elegans gene tmem-131, deficiency of which impairs collagen production and activates ER stress response. TMEM-131 N-termini contain bacterial PapD chaperone-like (PapD-L) domains essential for collagen assembly and secretion. Human TMEM131 binds to COL1A2 and TRAPPC8 via N-terminal PapD-L and C-terminal domain, respectively, to drive collagen production. We provide evidence that previously undescribed roles of TMEM131 in collagen recruitment and secretion are evolutionarily conserved in C. elegans, Drosophila and humans.

Abstract 467: ATF6B and ATF6A Play Complimentary Roles in Mediating Adaptive and Maladaptive Signaling in Cardiac Myocytes

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Shivsmriti Koul ◽  
Jung-kang Jin ◽  
Clifford M Hogan ◽  
Christopher C Glembotski
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Stress Response ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemic Heart ◽  
Neonatal Rat ◽  
Loss Of Function ◽  
Er Stress Response ◽  
Stress Response Genes

Rationale: ATF6α and ATF6β are endoplasmic reticulum (ER) transmembrane proteins that sense the accumulation of toxic misfolded proteins in the ER of cardiomyocytes, which can be brought about by ER stresses as ischemia. Upon ER stress, ATF6α is proteolytically cleaved into a transcription factor that binds to ER stress response elements (ERSEs) and increases expression of cardioprotective genes that restore ER protein folding. If ER proteostasis is not restored, maladaptive signaling is initiated. ATF6β is also proteolytically cleaved during ER stress, binds to the same ERSEs as ATF6α, but does not induce transcription. Hence it is clear from the above studies done in cancer cells that there are some marked similarities and differences between ATF6α and ATF6β. However, the relative roles of ATF6α and ATF6β have not been studied in the heart, where they might work in concert to mediate the dynamic switch from adaptive to maladaptive gene programing during myocardial pathology. Methods: We used neonatal rat ventricular myocytes (NRVMs) to explore the effects of ATF6α or ATF6β loss-of-function in cells treated with the ER stressor, thapsigargin (TG), which mimics ischemic heart disease. Results: In NRVM treated with TG, knockdown of ATF6β resulted in much more pronounced cell death in isolated myocytes than knockdown of ATF6α. Consistent with this finding, transcriptome analyses showed that compared to knocking down ATF6α, knockdown of ATF6β upregulated much more maladaptive, cell death-inducing genes and downregulated more cardioprotective genes. Surprisingly, knockdown of either ATF6α or ATF6β downregulated some common adaptive ER stress response genes, such as GRP78 and Derlin while also upregulating common maladaptive ER stress response genes, such as CHOP, Bcl2, Bax. Conclusion: These data indicate that both ATF6α and ATF6 β are needed for optimal viability of NRVM subjected to ER stress. There is a common, as well as differential gene regulation program controlled by these two isoforms of ATF6. Importantly, this study demonstrates a novel mechanism by which these two isoforms of ATF6 interact to govern the progression from adaptive to maladaptive ER stress signaling during chronic misfolding of ER proteins that occurs in ischemic heart disease.

scholarly journals Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells

Oncogene ◽  
2002 ◽  
Vol 21 (57) ◽  
pp. 8749-8758 ◽  
Author(s):  
Takehiko Segawa ◽  
Martin E Nau ◽  
Linda L Xu ◽  
Rao N Chilukuri ◽  
Mazen Makarem ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Induced Expression ◽  
Er Stress Response ◽  
Stress Response Genes

Elongin functions as a loading factor for Mediator at ATF6α-regulated ER stress response genes

2021 ◽  
Vol 118 (39) ◽  
pp. e2108751118
Author(s):  
Yanfeng He ◽  
Shigeo Sato ◽  
Chieri Tomomori-Sato ◽  
Shiyuan Chen ◽  
Zach H. Goode ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stress Response ◽  
Er Stress ◽  
Rna Polymerase Ii ◽  
Transcription Activation ◽  
Bzip Transcription Factor ◽  
Er Stress Response ◽  
Stress Response Genes ◽  
Biochemical Studies ◽  
Rna Polymerase Ii Transcription

The bZIP transcription factor ATF6α is a master regulator of endoplasmic reticulum (ER) stress response genes. In this report, we identify the multifunctional RNA polymerase II transcription factor Elongin as a cofactor for ATF6α-dependent transcription activation. Biochemical studies reveal that Elongin functions at least in part by facilitating ATF6α-dependent loading of Mediator at the promoters and enhancers of ER stress response genes. Depletion of Elongin from cells leads to impaired transcription of ER stress response genes and to defects in the recruitment of Mediator and its CDK8 kinase subunit. Taken together, these findings bring to light a role for Elongin as a loading factor for Mediator during the ER stress response.

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