Autophagic Elimination of Misfolded Procollagen Aggregates in the Endoplasmic Reticulum as a Means of Cell Protection

Abstract

Type I collagen is a major component of the extracellular matrix, and mutations in the collagen gene cause several matrix-associated diseases. These mutant procollagens are misfolded and often aggregated in the endoplasmic reticulum (ER). Although the misfolded procollagens are potentially toxic to the cell, little is known about how they are eliminated from the ER. Here, we show that procollagen that can initially trimerize but then aggregates in the ER are eliminated by an autophagy-lysosome pathway, but not by the ER-associated degradation (ERAD) pathway. Inhibition of autophagy by specific inhibitors or RNAi-mediated knockdown of an autophagy-related gene significantly stimulated accumulation of aggregated procollagen trimers in the ER, and activation of autophagy with rapamycin resulted in reduced amount of aggregates. In contrast, a mutant procollagen which has a compromised ability to form trimers was degraded by ERAD. Moreover, we found that autophagy plays an essential role in protecting cells against the toxicity of the ERAD-inefficient procollagen aggregates. The autophagic elimination of aggregated procollagen occurs independently of the ERAD system. These results indicate that autophagy is a final cell protection strategy deployed against ER-accumulated cytotoxic aggregates that are not able to be removed by ERAD.

Protein Folding and Quality Control in the ER

“…We have reported previously that the aggregated or insoluble form of type I collagen in the ER is degraded by autophagy-mediated lysosomal degradation, whereas nonaggregated forms are subject to ERAD (Fig. 1E) (Ishida et al 2009). When ERAF/ERAD or ubiquitin proteasome activities are compromised, autophagy is triggered via signaling pathways that usually involve unfolded protein response (UPR)-dependent elements (Ogata et al 2006;Fujita et al 2007;Hosokawa et al 2007;Kouroku et al 2007;Yorimitsu and Klionsky 2007b).…”

Osteogenesis imperfecta

“…The C terminal MLBR3 is especially crucial for interactions of collagen with extracellular matrix pro teins; substitutions in this domain impair extracellular matrix organization and have predominantly lethal out comes 36,37 . Mutations in the C propeptide that impair α chain recognition are responsible for ER associated protein degradation activation, which favours the removal of unassembled chains 29 . In the α2(I) chain, lethal regions that align with proteoglycan binding sites on collagen fibrils have been identified along the chain; mutations in these domains may severely affect proper matrix assembly 36,37 .…”

Smoke Exposure Causes Endoplasmic Reticulum Stress and Lipid Accumulation in Retinal Pigment Epithelium through Oxidative Stress and Complement Activation

“…Acute and chronic smoke exposure can adversely affect protein synthesis (29), lipid metabolism (30), and calcium homeostasis (78), resulting in ER stress. Specifically, smoking results in misfolding of nascent polypeptides in the ER as well as accumulation of protein aggregates; both of which trigger specific compensatory mechanisms to reduce or reverse the accumulation of unfolded proteins (unfolded protein response, UPR) (31), or removal of protein aggregates (autophagy) (32), respectively. Interestingly, in passive Heymann nephritis, a model of membranous nephropathy, membrane attack complex-induced podocyte injury has been found to be associated with and might be mediated by ER stress (summarized by Ref.…”