Loss of Collagen Related to the Cuticle Annular Furrow Activates Systemic Autophagy Hong Zhang State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China In response to environmental stresses, autophagy activity is modulated to maintain cell, tissue and organism homeostasis. The mechanisms that coordinately regulate autophagy activity among different cells and tissues remain largely unknown. In C. elegans, the cuticle acts as a barrier that protects tissues from exposure to the harsh external environment while also maintaining tissue shape and integrity. The cuticle is constituted mainly by collagens, which belong to two discrete interacting groups that form functionally distinct matrix substructures, annuli and annular furrows. Hemidesmosome-like junctions attach the epidermis to the extracellular matrix to ensure muscle anchoring to the cuticular exoskeleton. Here we demonstrated that loss of function of dpy-10 family genes, which encode collagens and are essential for formation of annular furrows in the cuticle, activates systemic autophagy activity. Autophagic degradation of SQST-1/p62 aggregates in hypodermis, intestinal cells, muscles and neurons is greatly enhanced. Depletion of dpy-10 causes disruption of hemidesmosomes, which also activates autophagy in hypodermal, muscle and intestine cells. In addition, cilia from neurons that are in touch with the cuticle structures are involved in inducing autophagy in hypodermis, muscles, intestine and neurons. We further showed that AAK-2/AMPK is activated by PAR-4 and is required for elevated autophagy in a cell-autonomous manner in dpy-10 mutants in hypodermis, muscles and intestine. Our results revealed that multiple signaling cascades impinge on AAK-2/AMPK to systemically activate autophagy.
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