A Novel Role for Decorin in Autophagy and Metabolism
Decorin is a multi-faceted class I small, leucine-rich proteoglycan found ubiquitously in the extracellular matrix. While originally identified as a regulator of collagen fibrillogenesis, decorin has since gained notoriety for its function in outside-in receptor tyrosine kinase signaling where it modulates numerous physiological functions including wound healing, inflammation, development, angiogenesis, cell adhesion, and tumorigenesis, among many others. These functions are intimately related to its wideranging interactome and have allowed decorin to become one of the most wellcharacterized of all proteoglycans, as well as one of the most physiologically relevant. Recently, decorin emerged as a mediator of endothelial cell autophagy and tumor cell mitophagy. These findings established decorin as a soluble paracrine effector where it plays a pivotal role in the regulation of a vital catabolic process inside the cell via RTK-mediated signaling. Following the acquisition of these initial data, we made a novel and serendipitous discovery that decorin mRNA and protein are induced in vivo by nutrient deprivation, an autophagic stimulus. Indeed, direct mTOR inhibition via the small molecule inhibitor, Torin 1, similarly increases decorin expression in vitro, implicating the canonical mTOR pathway as the mechanism for concurrent induction of decorin in the setting of autophagy. These data are quite significant since, for the first time, we demonstrate that a proteoglycan is inducible by autophagic stimuli. Furthermore and most remarkably, Dcn-/- mice display impaired cardiac autophagy following fasting vis-à-vis wild-type mice. Specifically, induction of the proautophagic gene, Map1lc3a, and formation of the lipidated form of its protein product, microtubule-associated light chain protein 3 (LC3), a marker of autophagosomes, are attenuated. Moreover, starvation-inducible genes including Cdkn1a and Atf4 are blunted in fasted Dcn-/- cardiac tissue. Importantly, systemic treatment of Dcn-/- mice with recombinant decorin completely rescues the cardiac autophagic impairment both at the gene and protein level, as well as rescues induction of Cdkn1a following fasting, verifying the importance of decorin in vivo for modulating not only autophagy but other critical intracellular signaling pathways as well. As autophagy impairment is linked to metabolic syndrome, it is unsurprising that we recently found that Dcn-/- mice display aberrant cardiac metabolism when compared to their wild-type counterparts, especially in the fasted state. These differences in metabolism are particularly prominent in glucose utilization pathways such as glycolysis, the citric acid cycle, the pentose phosphate pathway, and the hexosamine biosynthetic pathway. Functionally, wild-type mice demonstrate reduced ejection fraction following fasting whereas ejection fraction is sustained in fasted Dcn-/- mice. Notably, this preserved ejection fraction can be reversed upon decorin treatment. These findings may be related to both the autophagy and metabolic phenotype of the Dcn-/- mice and are part of ongoing work to decipher the connection between this soluble extracellular matrix proteoglycan and normal and anomalous cardiac function in response to physiological stressors, like starvation. Interestingly, decorin is not unique with regard to its ability to regulate autophagy. Other matrix constituents, like the large basement membrane proteoglycan, perlecan, are also members of an intricate nexus in the autophagic pathway. Unlike decorin, perlecan is anti-autophagic and pro-angiogenic. However, its C-terminal fragment, endorepellin, exhibits pro-autophagic properties similar to decorin via inhibition of canonical mTOR signaling to induce common autophagic intermediates. Furthermore, endorepellin has long been known to be a potent inhibitor of angiogenesis. Recently, we revealed that induction of autophagy is a partial mechanism for angiostasis in response to endorepellin treatment, making it an attractive endogenous molecule that may prove useful for combating tumor angiogenesis in a clinical setting. Thus, we present two prominent matrix molecules, decorin and endorepellin, as important signaling effectors for autophagy. This novel function of these two matrix factors may be key for understanding normal physiology as well as disease. Importantly, upcoming studies will likely uncover new therapeutic targets and unique treatment options for diseases, such as cancer, diabetes, and neurodegeneration, in which autophagy is impaired.
Gubbiotti, Maria Alexandria, "A Novel Role for Decorin in Autophagy and Metabolism" (2019). ETD Collection for Thomas Jefferson University. AAI10602881.