title: CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model.
abstract: Chronic stress in the endoplasmic reticulum (ER) underlies many degenerative and metabolic diseases involving apoptosis of vital cells. A well-established example is autosomal dominant retinitis pigmentosa (ADRP), an age-related retinal degenerative disease caused by mutant rhodopsins. Similar mutant alleles of Drosophila Rhodopsin-1 also impose stress on the ER and cause age-related retinal degeneration in that organism. Well-characterized signalling responses to ER stress, referred to as the unfolded protein response (UPR), induce various ER quality control genes that can suppress such retinal degeneration. However, how cells activate cell death programs after chronic ER stress remains poorly understood. Here, we report the identification of a signalling pathway mediated by cdk5 and mekk1 required for ER-stress-induced apoptosis. Inactivation of these genes specifically suppressed apoptosis, without affecting other protective branches of the UPR. CDK5 phosphorylates MEKK1, and together, they activate the JNK pathway for apoptosis. Moreover, disruption of this pathway can delay the course of age-related retinal degeneration in a Drosophila model of ADRP. These findings establish a previously unrecognized branch of ER-stress response signalling involved in degenerative diseases.
authors.affiliation: Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Kang
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Chung
authors.forename: Hyung Don
authors.initials: HD
authors.lastname: Ryoo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000172:deficiency / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005799:Genes, Dominant; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012243:Rhodopsin / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors
chemical_list: D029721:Drosophila Proteins; D012243:Rhodopsin; D051360:Cyclin-Dependent Kinase 5; C495904:Cdk5 protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1