The plakin domain of C. elegans VAB-10/plectin acts as a hub in a mechanotransduction pathway to promote morphogenesis

Mechanical forces control many cellular processes by eliciting a mechanotransduction response in target cells. The initial steps of mechanotransduction at hemidesmosomes remain undefined in contrast to focal adhesions and adherens junctions. Here, we focus on the C. elegans plectin homolog VAB-10A, the only evolutionary conserved hemidesmosome component. In C. elegans, muscle contractions induce a mechanotransduction pathway in the epidermis through hemidesmosomes. We used CRISPR to precisely remove spectrin repeats (SR) or a partially hidden Src-homology-3 (SH3) domain within the VAB-10 plakin domain. Deleting the SH3 or SR8 domains in combination with mutations affecting mechanotransduction, or just part of SR5 shielding the SH3 domain induced embryonic elongation arrest because hemidesmosomes collapse. Notably, recruitment of GIT-1, the first mechanotransduction player, requires the SR5 domain and the hemidesmosome transmembrane receptor LET-805. Furthermore, Molecular Dynamics simulations confirmed that forces acting on VAB-10 can render the central SH3 domain, otherwise in contact with SR4, available for interaction. Collectively, our data strongly argue that the plakin domain plays a central role in mechanotransduction and raise the possibility that VAB-10/plectin might act as a mechanosensor.\n\nSummary statementCRISPR-derived deletions reveal the roles of three spectrin repeats and an atypical SH3 domain from the plakin domain of the VAB-10 hemidesmosome component in mechanotransduction during C. elegans morphogenesis