Abstract
Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-β to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Similarly, the mammalian CK counterpart, MYO7A, binds to and impinges on CASPASE-8, revealing a new regulatory axis affecting receptor interacting protein kinase-1 (RIPK1)>CASPASE-8 signalling. Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events.
Highlights
Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration
Our finding that MYO7A interacts with the initiator CASP8 and dampens its activation may help to explain why patients with mutations in MYO7A suffer progressive loss of sensory neurons
Reciprocal co-immunoprecipitation assays demonstrated that CK associated with DRONC, while it did not interact with green fluorescent protein (GFP), DIAP1 or drICE (Fig. 1b,c)
Summary
Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. We find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-b to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Our data demonstrate that the Drosophila myosin family member CRINKLED (CK) and its mammalian counterpart Myosin VIIA (MYO7A) act as substrate adaptor for kinases, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. In mammals, this results in inactivation of RIPK1 and suppression of CASP8. Given that RIPK1 and CASP8 take part in the defense of homeostasis downstream of many cytokine receptors, it is plausible that inflammatory signals contribute to the onset and progression of retinitis pigmentosa in patients with MYO7A mutations due to aberrant activation of RIPK1-dependent cell death
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