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.

蛋白聚糖和选定的细胞外基质成分正在成为进化逆转的细胞内分解代谢途径的内在和关键调节剂。通常，这些分泌的分子会在多种细胞类型、组织和模型系统中引起持续的自噬。蛋白多糖的独特性质带来了范式转变，拓宽了我们对基质介导的信号级联的理解。控制自噬的动态细胞途径现在与嵌入复杂的基质分子网络中的同样动态且流动的信号网络相连。一个快速新兴的研究领域涵盖多种基质衍生候选物，代表一系列可溶性基质成分，包括核心蛋白聚糖、双糖链蛋白聚糖、内皮素、内皮抑素、VI 型胶原和纤溶酶原 kringle 5。这些基质成分具有促自噬作用，同时具有抗血管生成作用。相反，基底膜聚糖、层粘连蛋白α2链和lumican具有抗自噬功能。从机制上讲，与细胞内分解代谢事件相关的每种基质成分都与特定的细胞表面受体结合，该受体通常聚集在自噬机制的共同核心上，包括 AMPK、Peg3 和 Beclin 1。我们认为这种基质诱发的自噬是非典型的，因为它发生了以变​​构方式，并且独立于营养物质的可用性或普遍的生物能学控制。我们认为基质调节的自噬是维持适当组织稳态的重要的由外而内的信号传导机制，可用于治疗多种疾病。