Translational Induction of the Inhibitor of Apoptosis Protein HIAP2 during Endoplasmic Reticulum Stress Attenuates Cell Death and Is Mediated via an Inducible Internal Ribosome Entry Site Element

ABSTRACT X-linked inhibitor of apoptosis protein (XIAP) is a key regulator of programmed cell death triggered by various apoptotic triggers. Translation of XIAP is controlled by a 162-nucleotide (nt) internal ribosome entry site (IRES) element located in the 5′ untranslated region of XIAP mRNA. XIAP IRES mediates efficient translation of XIAP under physiological stress and enhances cell protection against serum deprivation and radiation-induced apoptosis. In the present report we describe the assembly of a sequence-specific RNA-protein complex consisting of at least four cytosolic proteins on the XIAP IRES element. We determine that the core binding sequence is approximately 28 nt long and is located 34 nt upstream of the initiation site. Moreover, we identify the La autoantigen as a protein that specifically bindsXIAP IRES in vivo and in vitro. The biological relevance of this interaction is further demonstrated by the inhibition ofXIAP IRES-mediated translation in the absence of functional La protein. The results suggest an important role for the La protein in the regulation of XIAP expression, possibly by facilitating ribosome recruitment to the XIAP IRES.

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Pseudomonas aeruginosaDelays Kupffer Cell Death via Stabilization of the X-Chromosome-Linked Inhibitor of Apoptosis Protein

The Journal of Immunology ◽

10.4049/jimmunol.179.1.505 ◽

2007 ◽

Vol 179 (1) ◽

pp. 505-513 ◽

Cited By ~ 7

Author(s):

Alix Ashare ◽

Martha M. Monick ◽

Amanda B. Nymon ◽

John M. Morrison ◽

Matthew Noble ◽

...

Keyword(s):

Cell Death ◽

X Chromosome ◽

Kupffer Cell ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

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Diablo Promotes Apoptosis by Removing Miha/Xiap from Processed Caspase 9

The Journal of Cell Biology ◽

10.1083/jcb.152.3.483 ◽

2001 ◽

Vol 152 (3) ◽

pp. 483-490 ◽

Cited By ~ 128

Author(s):

Paul G. Ekert ◽

John Silke ◽

Christine J. Hawkins ◽

Anne M. Verhagen ◽

David L. Vaux

Keyword(s):

Cell Death ◽

Cytochrome C ◽

Caspase 3 ◽

Direct Interaction ◽

Inhibitor Of Apoptosis ◽

Caspase 9 ◽

Inhibitor Of Apoptosis Protein ◽

Grim Reaper ◽

Apoptosis Protein ◽

Mammalian Protein

MIHA is an inhibitor of apoptosis protein (IAP) that can inhibit cell death by direct interaction with caspases, the effector proteases of apoptosis. DIABLO is a mammalian protein that can bind to IAPs and antagonize their antiapoptotic effect, a function analogous to that of the proapoptotic Drosophila molecules, Grim, Reaper, and HID. Here, we show that after UV radiation, MIHA prevented apoptosis by inhibiting caspase 9 and caspase 3 activation. Unlike Bcl-2, MIHA functioned after release of cytochrome c and DIABLO from the mitochondria and was able to bind to both processed caspase 9 and processed caspase 3 to prevent feedback activation of their zymogen forms. Once released into the cytosol, DIABLO bound to MIHA and disrupted its association with processed caspase 9, thereby allowing caspase 9 to activate caspase 3, resulting in apoptosis.

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Protein kinase C stabilizes X-linked inhibitor of apoptosis protein (XIAP) through phosphorylation at Ser87 to suppress apoptotic cell death

Psychogeriatrics ◽

10.1111/j.1479-8301.2011.00355.x ◽

2011 ◽

Vol 11 (2) ◽

pp. 90-97 ◽

Cited By ~ 12

Author(s):

Kiyoko KATO ◽

Toshihisa TANAKA ◽

Golam SADIK ◽

Miyako BABA ◽

Daisuke MARUYAMA ◽

...

Keyword(s):

Cell Death ◽

Protein Kinase C ◽

Protein Kinase ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Protein ◽

Kinase C ◽

Apoptosis Protein

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Human Cytomegalovirus Induces the Endoplasmic Reticulum Chaperone BiP through Increased Transcription and Activation of Translation by Using the BiP Internal Ribosome Entry Site

Journal of Virology ◽

10.1128/jvi.01330-10 ◽

2010 ◽

Vol 84 (21) ◽

pp. 11479-11486 ◽

Cited By ~ 29

Author(s):

Nicholas J. Buchkovich ◽

Yongjun Yu ◽

Francis J. Pierciey ◽

James C. Alwine

Keyword(s):

Endoplasmic Reticulum ◽

Transcriptional Activation ◽

Internal Ribosome Entry Site ◽

Hcmv Infection ◽

Mrna Translation ◽

Entry Site ◽

Internal Ribosome Entry ◽

Unfolded Protein ◽

Infected Cells ◽

Protein Response

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.

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