Abstract
Epidermal barrier epithelia form a first line of defense against the environment, protecting animals against infection and repairing physical damage. In C. elegans, death-associated protein kinase (DAPK-1) regulates epidermal morphogenesis, innate immunity and wound repair. Combining genetic suppressor screens and pharmacological tests, we find that DAPK-1 maintains epidermal tissue integrity through regulation of the microtubule (MT) cytoskeleton. dapk-1 epidermal phenotypes are suppressed by treatment with microtubule-destabilizing drugs and mimicked or enhanced by microtubule-stabilizing drugs. Loss of function in ptrn-1, the C. elegans member of the Patronin/Nezha/CAMSAP family of MT minus-end binding proteins, suppresses dapk-1 epidermal and innate immunity phenotypes. Over-expression of the MT-binding CKK domain of PTRN-1 triggers epidermal and immunity defects resembling those of dapk-1 mutants, and PTRN-1 localization is regulated by DAPK-1. DAPK-1 and PTRN-1 physically interact in co-immunoprecipitation experiments, and DAPK-1 itself undergoes MT-dependent transport. Our results uncover an unexpected interdependence of DAPK-1 and the microtubule cytoskeleton in maintenance of epidermal integrity.
Highlights
Death-associated protein kinase 1 (DAPK1) and its related calcium-regulated serine/threonine kinases play a wide variety of roles in cell death and tumor suppression (Bialik and Kimchi, 2006)
The Mor phenotype reflects a progressive accumulation of the cuticle and degeneration of the underlying epidermis at the extreme anterior and posterior, as well as the dorsal midline. dapk-1(ju4), which causes a missense alteration S179L in the DAPK-1 kinase domain, causes 100% of animals to display this aberrant morphology
These analyses suggest that aberrant dapk-1 function causes epidermal integrity to be sensitized to MT stability. dapk-1(ju4) defects were not suppressed by loss of function in several other genes implicated in MT dynamics (Table 1), suggesting a specific subset of MT regulators can affect epidermal morphogenesis
Summary
Death-associated protein kinase 1 (DAPK1) and its related calcium-regulated serine/threonine kinases play a wide variety of roles in cell death and tumor suppression (Bialik and Kimchi, 2006). Mammalian DAPK1 has been implicated in stress responses (Tu et al, 2010), antiviral immunity (Zhang et al.), and in IL-1ß-associated inflammatory diseases (Chakilam et al, 2013; Chuang et al, 2011). DAPK-1 regulates epidermal development and wound repair, independently of known cell death programs. Mutations in dapk result in progressive degeneration of the epidermis, cuticle hypertrophy, and constitutive activation of epidermal innate immune responses via a p38 MAPK cascade (Tong et al, 2009). Such dapk mutants behave as if they are constitutively wounded even without injury, and when wounded exhibit faster wound repair (Xu and Chisholm, 2011). How DAPK-1 regulates these multiple aspects of epidermal maintenance and wound repair is not yet understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
