Cdk5 and Mekk1 mediate a Pro-Apoptotic Signaling Response to Endoplasmic Reticulum Stress in a Drosophila Model of Autosomal Dominant Retinitis Pigmentosa

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 (1, 2). Similar mutant alleles of Drosophila rhodopsin-1 also impose stress on the ER and cause age-related retinal degeneration in that organism (3). Well-characterized signaling responses to ER-stress, referred to as the Unfolded Protein Response (UPR) (4), induce various ER quality control genes that can suppress such retinal degeneration (5). However, how cells activate cell death programs after chronic ER-stress remains poorly understood. Here, we report the identification of a signaling 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, 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 signaling involved in degenerative diseases.