scholarly journals Internal ribosome entry site-mediated translational regulation of ATF4 splice variant in mammalian unfolded protein response

2013 ◽  
Vol 1833 (10) ◽  
pp. 2165-2175 ◽  
Author(s):  
Ching-Ping Chan ◽  
Kin-Hang Kok ◽  
Hei-Man Vincent Tang ◽  
Chi-Ming Wong ◽  
Dong-Yan Jin
2010 ◽  
Vol 84 (21) ◽  
pp. 11479-11486 ◽  
Author(s):  
Nicholas J. Buchkovich ◽  
Yongjun Yu ◽  
Francis J. Pierciey ◽  
James C. Alwine

ABSTRACT The endoplasmic reticulum (ER) chaperone BiP (immunoglobulin binding protein) plays a major role in the control of the unfolded protein response. We have previously shown that BiP levels are dramatically increased during human cytomegalovirus (HCMV) infection, where BiP performs unique roles in viral assembly and egress. We show that BiP mRNA levels increase during infection due to activation of the BiP promoter by the major immediate-early (MIE) proteins. The BiP promoter, like other ER stress-activated promoters, contains endoplasmic reticulum stress elements (ERSEs), which are activated by unfolded protein response (UPR)-induced transcription factors. However, these elements are not needed for MIE protein-mediated transcriptional activation; thus, a virus-specific transcriptional activation mechanism is used. Transcriptional activation results in only a 3- to 4-fold increase in BiP mRNA, suggesting that additional mechanisms for BiP production are utilized. The BiP mRNA contains an internal ribosome entry site (IRES) which increases the level of BiP mRNA translation. We show that utilization of the BiP IRES is dramatically increased in HCMV-infected cells. Utilization of the BiP IRES can be activated by the La autoantigen, also called Sjögren's syndrome antigen B (SSB). We show that SSB/La levels are significantly increased during HCMV infection, and SSB/La depletion causes the loss of BiP IRES utilization and lowers endogenous BiP levels in infected cells. Our data show that BiP levels increase in HCMV-infected cells through the combination of increased BiP gene transcription mediated by the MIE proteins and increased BiP mRNA translation due to SSB/La-induced utilization of the BiP IRES.


2010 ◽  
Vol 429 (3) ◽  
pp. 603-612 ◽  
Author(s):  
Fabrizio Damiano ◽  
Simone Alemanno ◽  
Gabriele V. Gnoni ◽  
Luisa Siculella

SREBPs (sterol-regulatory-element-binding proteins) are a family of transcription factors that modulate the expression of several enzymes implicated in endogenous cholesterol, fatty acid, triacylglycerol and phospholipid synthesis. In the present study, evidence for SREBP-1 regulation at the translational level is reported. Using several experimental approaches, we have demonstrated that the 5′-UTR (untranslated region) of the SREBP-1a mRNA contains an IRES (internal ribosome entry site). Transfection experiments with the SREBP-1a 5′-UTR inserted in a dicistronic reporter vector showed a remarkable increase in the downstream cistron translation, through a cap-independent mechanism. Insertion of the SREBP-1c 5′-UTR in the same vector also stimulated the translation of the downstream cistron, but the observed effect can be ascribed, at least in part, to a cryptic promoter activity. Cellular stress conditions, such as serum starvation, caused an increase in the level of SREBP-1 precursor and mature form in both Hep G2 and HeLa cells, despite the overall reduction in protein synthesis, whereas mRNA levels for SREBP-1 were unaffected by serum starvation. Transfection experiments carried out with a dicistronic construct demonstrated that the cap-dependent translation was affected more than IRES-mediated translation by serum starvation. The thapsigargin- and tunicamycin-induced UPR (unfolded protein response) also increased SREBP-1 expression in Hep G2 cells, through the cap-independent translation mediated by IRES. Overall, these findings indicate that the presence of IRES in the SREBP-1a 5′-UTR allows translation to be maintained under conditions that are inhibitory to cap-dependent translation.


2000 ◽  
Vol 5 (5) ◽  
pp. 897-904 ◽  
Author(s):  
Heather P Harding ◽  
Yuhong Zhang ◽  
Anne Bertolotti ◽  
Huiqing Zeng ◽  
David Ron

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Muneshige Tokugawa ◽  
Yasumichi Inoue ◽  
Kan’ichiro Ishiuchi ◽  
Chisane Kujirai ◽  
Michiyo Matsuno ◽  
...  

AbstractThe unfolded protein response (UPR) controls protein homeostasis through transcriptional and translational regulation. However, dysregulated UPR signaling has been associated with the pathogenesis of many human diseases. Therefore, the compounds modulating UPR may provide molecular insights for these pathologies in the context of UPR. Here, we screened small-molecule compounds that suppress UPR, using a library of Myanmar wild plant extracts. The screening system to track X-box binding protein 1 (XBP1) splicing activity revealed that the ethanol extract of the Periploca calophylla stem inhibited the inositol-requiring enzyme 1 (IRE1)-XBP1 pathway. We isolated and identified periplocin as a potent inhibitor of the IRE1-XBP1 axis. Periplocin also suppressed other UPR axes, protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Examining the structure–activity relationship of periplocin revealed that cardiac glycosides also inhibited UPR. Moreover, periplocin suppressed the constitutive activation of XBP1 and exerted cytotoxic effects in the human multiple myeloma cell lines, AMO1 and RPMI8226. These results reveal a novel suppressive effect of periplocin or the other cardiac glycosides on UPR regulation, suggesting that these compounds will contribute to our understanding of the pathological or physiological importance of UPR.


2003 ◽  
Vol 17 (10) ◽  
pp. 1959-1971 ◽  
Author(s):  
Cristina Rabadan-Diehl ◽  
Simona Volpi ◽  
Maria Nikodemova ◽  
Greti Aguilera

FEBS Letters ◽  
2008 ◽  
Vol 582 (4) ◽  
pp. 503-509 ◽  
Author(s):  
Tom Payne ◽  
Colin Hanfrey ◽  
Amy L. Bishop ◽  
Anthony J. Michael ◽  
Simon V. Avery ◽  
...  

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