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PMID:14752510

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Citation

Gotoh, T, Terada, K, Oyadomari, S and Mori, M (2004) hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria. Cell Death Differ. 11:390-402

Abstract

We reported that the endoplasmic reticulum (ER) stress pathway involving CHOP, a member of the C/EBP transcription factor family, plays a key role in nitric oxide (NO)-mediated apoptosis of macrophages and pancreatic beta cells. We also showed that the cytosolic chaperone pair of hsp70 and dj1 (hsp40/hdj-1) or dj2 (HSDJ/hdj-2) prevents NO-mediated apoptosis upstream of cytochrome c release from mitochondria. To analyze roles of the chaperone pair in preventing apoptosis, RAW 264.7 macrophages stably expressing hsp70 and dj1 or dj2 were established. The chaperone pair prevented LPS/IFN-gamma-induced and NO-mediated apoptosis downstream of CHOP induction. hsp70 mutant protein lacking the ATPase domain or the C-terminal EEVD sequence were not effective in preventing CHOP-induced apoptosis. A mutant dj2 lacking the C-terminal prenylation CaaX motif, was also not effective. When wild-type RAW 264.7 cells were treated with LPS/IFN-gamma, NO-mediated apoptosis was induced, and proapoptotic Bcl-2 family protein Bax was translocated from cytosol to mitochondria. This translocation was prevented in cells stably expressing hsp70/dj2, and in CHOP knockout cells. Overexpression of CHOP in wild-type cells also induced translocation of Bax and this translocation was prevented in cells expressing hsp70/dj2. CHOP-induced apoptosis was prevented by Bax knock-down. Coimmunoprecipitation experiments showed that Bax interacts with both hsp70 and dj1/dj2. ATPase domain of hsp70 was necessary for the binding with Bax. These findings indicate that CHOP-induced apoptosis is mediated by translocation of Bax from the cytosol to the mitochondria, and hsp70/dj1 or dj2 chaperone pair prevents apoptosis by interacting with Bax and preventing translocation to the mitochondria.

Links

PubMed Online version:10.1038/sj.cdd.4401369

Keywords

Adenosine Triphosphatases/metabolism; Animals; Apoptosis/physiology; CCAAT-Enhancer-Binding Proteins/antagonists & inhibitors; CCAAT-Enhancer-Binding Proteins/metabolism; COS Cells; Cell Line; Cercopithecus aethiops; Cytosol/metabolism; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins/genetics; HSP70 Heat-Shock Proteins/physiology; Heat-Shock Proteins/genetics; Heat-Shock Proteins/physiology; Macrophages/cytology; Macrophages/metabolism; Mice; Mice, Knockout; Mitochondria/metabolism; Molecular Chaperones/metabolism; Molecular Chaperones/pharmacology; Nitric Oxide/antagonists & inhibitors; Protein Transport/physiology; Proto-Oncogene Proteins/antagonists & inhibitors; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-bcl-2; Transcription Factor CHOP; Transcription Factors/antagonists & inhibitors; Transcription Factors/metabolism; Transfection; bcl-2-Associated X Protein

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ATF6A

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DNJA1

enables

GO:0030957: Tat protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q07813

F

  • has_input:(UniProtKB:Q07812)

Seeded From UniProt

complete

HUMAN:DNJA1

involved_in

GO:1905259: negative regulation of nitrosative stress-induced intrinsic apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000235)

Seeded From UniProt

complete

HUMAN:DNJA1

involved_in

GO:1903748: negative regulation of establishment of protein localization to mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DDIT3

involved_in

GO:1990442: intrinsic apoptotic signaling pathway in response to nitrosative stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DDIT3

involved_in

GO:0072655: establishment of protein localization to mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

P

  • transports_or_maintains_localization_of:(UniProtKB:Q07813)
  • part_of:(GO:0043065)

Seeded From UniProt

complete

MOUSE:DDIT3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000235)

Seeded From UniProt

complete

MOUSE:DNJA1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q07813

F

Seeded From UniProt

complete

MOUSE:BAX

enables

GO:0030544: Hsp70 protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:BAX

enables

GO:0051087: chaperone binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P63037

F

Seeded From UniProt

complete

MOUSE:BAX

enables

GO:0051087: chaperone binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99LX0

F

Seeded From UniProt

complete

MOUSE:BAX

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31689

F

  • has_input:(UniProtKB:P63037)

Seeded From UniProt

complete

MOUSE:BAX

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:1905259: negative regulation of nitrosative stress-induced intrinsic apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0000235)

Seeded From UniProt

complete

MOUSE:PARK7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q07813

F

Seeded From UniProt

complete

HUMAN:PARK7

involved_in

GO:1905259: negative regulation of nitrosative stress-induced intrinsic apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000235)

Seeded From UniProt

complete

MOUSE:BAX

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:BAX

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

exists_during:(GO:0006915)

Seeded From UniProt

complete

MOUSE:BAX

enables

GO:0030544: Hsp70 protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

happens_during:(GO:0033554)

Seeded From UniProt

complete

MOUSE:BAX

enables

GO:0051087: chaperone binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99LX0

F

happens_during:(GO:0033554)

Seeded From UniProt

complete

MOUSE:BAX

enables

GO:0051087: chaperone binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P63037

F

happens_during:(GO:0033554)

Seeded From UniProt

complete

HUMAN:DNJA1

enables

GO:0051087: chaperone binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DNJA1

involved_in

GO:0070585: protein localization to mitochondrion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DNJA1

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DNJA1

enables

GO:0030544: Hsp70 protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DNJA1

involved_in

GO:0051223: regulation of protein transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DNJA1

involved_in

GO:1905259: negative regulation of nitrosative stress-induced intrinsic apoptotic signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0000235)

Seeded From UniProt

complete

HUMAN:DNJA1

involved_in

GO:1903748: negative regulation of establishment of protein localization to mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

P

  • part_of:(GO:1905259)
  • has_regulation_target:(UniProtKB:Q07812)

Seeded From UniProt

complete

HUMAN:DNJA1

enables

GO:0030957: Tat protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q07813

F

has_input:(UniProtKB:Q07812)

Seeded From UniProt

complete

Notes

See also

References

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