Protein kinase RNA/FADD/caspase-8 pathway mediates the proapoptotic activity of the RNA-binding protein human antigen R (HuR)

Christopher Von Roretz, Imed Gallouzi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The RNA-binding protein human antigen R (HuR) has been implicated in apoptosis in multiple ways. Several studies have shown that in response to a variety of stresses HuR promotes the expression of proapoptotic mRNAs, whereas others reported its regulatory effect on antiapoptotic messages. We recently showed that in response to severe stress, HuR is cleaved to generate two cleavage products (CPs), HuR-CP1 (24 kDa) and HuR-CP2 (8 kDa), by which it promotes apoptotic cell death. Here, we show that this cleavage event is dependent on protein kinase RNA (PKR). Surprisingly, although in response to the apoptotic inducer staurosporine PKR itself is not phosphorylated, PKR triggers the cleavage of HuR via its downstream effector FADD that in turn activates the caspase-8/caspase-3 pathway. This effect, however, does not require the phosphorylation of the eukaryotic translation initiation factor 2α. Additionally, we observed that these HuR-CPs are sufficient to trigger cell death in the absence of activation of the PKR pathway. Therefore, our results support a model whereby in response to lethal stress, PKR, without being phosphorylated, activates the FADD/caspase-8/caspase-3 pathway to trigger HuR cleavage, and the HuR-CPs are then capable of promoting apoptosis.

Original languageEnglish
Pages (from-to)16806-16813
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number22
DOIs
Publication statusPublished - 28 May 2010
Externally publishedYes

Fingerprint

RNA-Binding Proteins
Caspase 8
Protein Kinases
RNA
Antigens
Cell death
Caspase 3
Cell Death
Prokaryotic Initiation Factor-2
Eukaryotic Initiation Factor-2
RNA Cleavage
eIF-2 Kinase
Apoptosis
Eukaryotic Initiation Factors
Phosphorylation
Staurosporine
Heat-Shock Proteins
Chemical activation
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Protein kinase RNA/FADD/caspase-8 pathway mediates the proapoptotic activity of the RNA-binding protein human antigen R (HuR). / Von Roretz, Christopher; Gallouzi, Imed.

In: Journal of Biological Chemistry, Vol. 285, No. 22, 28.05.2010, p. 16806-16813.

Research output: Contribution to journalArticle

@article{ceb259d815b1474fb47d68c7f497f4cc,
title = "Protein kinase RNA/FADD/caspase-8 pathway mediates the proapoptotic activity of the RNA-binding protein human antigen R (HuR)",
abstract = "The RNA-binding protein human antigen R (HuR) has been implicated in apoptosis in multiple ways. Several studies have shown that in response to a variety of stresses HuR promotes the expression of proapoptotic mRNAs, whereas others reported its regulatory effect on antiapoptotic messages. We recently showed that in response to severe stress, HuR is cleaved to generate two cleavage products (CPs), HuR-CP1 (24 kDa) and HuR-CP2 (8 kDa), by which it promotes apoptotic cell death. Here, we show that this cleavage event is dependent on protein kinase RNA (PKR). Surprisingly, although in response to the apoptotic inducer staurosporine PKR itself is not phosphorylated, PKR triggers the cleavage of HuR via its downstream effector FADD that in turn activates the caspase-8/caspase-3 pathway. This effect, however, does not require the phosphorylation of the eukaryotic translation initiation factor 2α. Additionally, we observed that these HuR-CPs are sufficient to trigger cell death in the absence of activation of the PKR pathway. Therefore, our results support a model whereby in response to lethal stress, PKR, without being phosphorylated, activates the FADD/caspase-8/caspase-3 pathway to trigger HuR cleavage, and the HuR-CPs are then capable of promoting apoptosis.",
author = "{Von Roretz}, Christopher and Imed Gallouzi",
year = "2010",
month = "5",
day = "28",
doi = "10.1074/jbc.M109.087320",
language = "English",
volume = "285",
pages = "16806--16813",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "22",

}

TY - JOUR

T1 - Protein kinase RNA/FADD/caspase-8 pathway mediates the proapoptotic activity of the RNA-binding protein human antigen R (HuR)

AU - Von Roretz, Christopher

AU - Gallouzi, Imed

PY - 2010/5/28

Y1 - 2010/5/28

N2 - The RNA-binding protein human antigen R (HuR) has been implicated in apoptosis in multiple ways. Several studies have shown that in response to a variety of stresses HuR promotes the expression of proapoptotic mRNAs, whereas others reported its regulatory effect on antiapoptotic messages. We recently showed that in response to severe stress, HuR is cleaved to generate two cleavage products (CPs), HuR-CP1 (24 kDa) and HuR-CP2 (8 kDa), by which it promotes apoptotic cell death. Here, we show that this cleavage event is dependent on protein kinase RNA (PKR). Surprisingly, although in response to the apoptotic inducer staurosporine PKR itself is not phosphorylated, PKR triggers the cleavage of HuR via its downstream effector FADD that in turn activates the caspase-8/caspase-3 pathway. This effect, however, does not require the phosphorylation of the eukaryotic translation initiation factor 2α. Additionally, we observed that these HuR-CPs are sufficient to trigger cell death in the absence of activation of the PKR pathway. Therefore, our results support a model whereby in response to lethal stress, PKR, without being phosphorylated, activates the FADD/caspase-8/caspase-3 pathway to trigger HuR cleavage, and the HuR-CPs are then capable of promoting apoptosis.

AB - The RNA-binding protein human antigen R (HuR) has been implicated in apoptosis in multiple ways. Several studies have shown that in response to a variety of stresses HuR promotes the expression of proapoptotic mRNAs, whereas others reported its regulatory effect on antiapoptotic messages. We recently showed that in response to severe stress, HuR is cleaved to generate two cleavage products (CPs), HuR-CP1 (24 kDa) and HuR-CP2 (8 kDa), by which it promotes apoptotic cell death. Here, we show that this cleavage event is dependent on protein kinase RNA (PKR). Surprisingly, although in response to the apoptotic inducer staurosporine PKR itself is not phosphorylated, PKR triggers the cleavage of HuR via its downstream effector FADD that in turn activates the caspase-8/caspase-3 pathway. This effect, however, does not require the phosphorylation of the eukaryotic translation initiation factor 2α. Additionally, we observed that these HuR-CPs are sufficient to trigger cell death in the absence of activation of the PKR pathway. Therefore, our results support a model whereby in response to lethal stress, PKR, without being phosphorylated, activates the FADD/caspase-8/caspase-3 pathway to trigger HuR cleavage, and the HuR-CPs are then capable of promoting apoptosis.

UR - http://www.scopus.com/inward/record.url?scp=77952750913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952750913&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.087320

DO - 10.1074/jbc.M109.087320

M3 - Article

VL - 285

SP - 16806

EP - 16813

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 22

ER -