A functional outside-in signaling network of proteoglycans and matrix molecules regulating autophagy

Proteoglycans and selected extracellular matrix constituents are emerging as intrinsic and critical regulators of evolutionarily conversed, intracellular catabolic pathways. Often, these secreted molecules evoke sustained autophagy in a variety of cell types, tissues, and model systems. The unique properties of proteoglycans have ushered in a paradigmatic shift to broaden our understanding of matrix-mediated signaling cascades. The dynamic cellular pathway controlling autophagy is now linked to an equally dynamic and fluid signaling network embedded in a complex meshwork of matrix molecules. A rapidly emerging field of research encompasses multiple matrix-derived candidates, representing a menagerie of soluble matrix constituents including decorin, biglycan, endorepellin, endostatin, collagen VI and plasminogen kringle 5. These matrix constituents are pro-autophagic and simultaneously anti-angiogenic. In contrast, perlecan, laminin α2 chain, and lumican have anti-autophagic functions. Mechanistically, each matrix constituent linked to intracellular catabolic events engages a specific cell surface receptor that often converges on a common core of the autophagic machinery including AMPK, Peg3 and Beclin 1. We consider this matrix-evoked autophagy as non-canonical given that it occurs in an allosteric manner and is independent of nutrient availability or prevailing bioenergetics control. We propose that matrix-regulated autophagy is an important outside-in signaling mechanism for proper tissue homeostasis that could be therapeutically leveraged to combat a variety of diseases.