MDG1/ERdj4, an ER-resident DnaJ family member, suppresses cell death induced by ER stress.
BACKGROUND
Alterations in homeostasis after various cellular stresses, which prevent protein folding and cause an accumulation of misfolding or malfolding proteins in the endoplasmic reticulum (ER), have the potential to induce cellular damage, and are therefore a type of 'ER stress.' To understand the molecular events or cascades underlying the ER stress response regulated by gene transcription and mediated by stress transducers, it is crucial to identify the molecules induced during ER stress and to analyse the roles of these genes.


RESULTS
We identified MDG1/ERdj4, a member of the DnaJ protein family, as an inducible gene during ER stress. MDG1/ERdj4 contains the J domain, which is essential for interacting with Hsp70s, at the N-terminal portion and just at the back of the transmembrane domain. Its trypsin digestion and glycosylation of a chimeric protein composed of MDG1/ERdj4 fused with the extracellular domain of the amyloid precursor protein at its C-terminus, showed that its C-terminal portion containing the J domain could be orientated to the ER lumen. Over-expression of it inhibited the cell death induced by ER stress. In contrast, its mutants with the J domain deleted showed no protective effects against cell death.


CONCLUSIONS
MDG1/ERdj4 may play roles in stabilizing GRP78/BiP binding to unfolded substrate proteins in a J domain-dependent manner and prevent the accumulation of unfolded proteins in the ER, consequently protecting cells from ER stress.
Kurisu
Junko
J
Division of Structural Cellular Biology, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan.
Honma
Asuka
A
Miyajima
Hiroshi
H
Kondo
Shinichi
S
Okumura
Masayo
M
Imaizumi
Kazunori
K
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D050956:HSP40 Heat-Shock Proteins; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma / Q000235:genetics; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; C478021:DNAJB9 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D050956:HSP40 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins