Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways.
When confronted with environmental stress, cells either activate defence mechanisms to survive, or initiate apoptosis, depending on the type of stress. Certain types of stress, such as hypoxia, heatshock and arsenite (type 1 stress), induce cells to assemble cytoplasmic stress granules (SGs), a major adaptive defence mechanism. SGs are multimolecular aggregates of stalled translation pre-initiation complexes that prevent the accumulation of mis-folded proteins. Type 2 stress, which includes X-rays and genotoxic drugs, induce apoptosis through the stress-activated p38 and JNK MAPK (SAPK) pathways. A functional relationship between the SG and SAPK responses is unknown. Here, we report that SG formation negatively regulates the SAPK apoptotic response, and that the signalling scaffold protein RACK1 functions as a mediator between the two responses. RACK1 binds to the stress-responsive MTK1 MAPKKK and facilitates its activation by type 2 stress; however, under conditions of type 1 stress, RACK1 is sequestered into SGs. Thus, type 1 conditions suppress activation of the MTK1-SAPK pathway and apoptosis induced by type 2 stress. These findings may be relevant to the problem of hypoxia-induced resistance to cancer chemotherapy.
Department of Molecular Cell Signaling, Institute of Medical Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Kyoko
K
Arimoto
Hiroyuki
H
Fukuda
Shinobu
S
Imajoh-Ohmi
Haruo
H
Saito
Mutsuhiro
M
Takekawa
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology; D019556:COS Cells; D002232:Carbocyanines / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D018384:Oxidative Stress; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D017304:Annexin A5; D018053:Arsenites; D002232:Carbocyanines; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D017670:Sodium Compounds; D013439:Sulfhydryl Reagents; C089187:cyanine dye 3; C007293:DAPI; C017947:sodium arsenite; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins