Collagen misfolding mutations: the contribution of the unfolded protein response to the molecular pathology

Mutations in collagen genes cause a broad range of connective tissue pathologies. Structural mutations that impact procollagen assembly or triple helix formation and stability are a common and important mutation class. How misfolded procollagens engage with the cellular proteostasis machinery and whether they can elicit a cytotoxic unfolded protein response (UPR) is a topic of considerable research interest. Such interest is well justified since modulating the UPR could offer a new approach to treat collagenopathies for which there are no current disease mechanism-targeting therapies. This review scrutinizes the evidence underpinning the view that endoplasmic reticulum stress and chronic UPR activation contributes significantly to the pathophysiology of the collagenopathies. While there is strong evidence that the UPR contributes to the pathology for collagen X misfolding mutations, the evidence that misfolding mutations in other collagen types induce a canonical, cytotoxic UPR is incomplete. To gain a more comprehensive understanding about how the UPR amplifies to pathology, and thus what types of manipulations of the UPR might have therapeutic relevance, much more information is needed about how specific misfolding mutation types engage differentially with the UPR and downstream signaling responses. Most importantly, since the capacity of the proteostasis machinery to respond to collagen misfolding is likely to vary between cell types, reflecting their functional roles in collagen and extracellular matrix biosynthesis, detailed studies on the UPR should focus as much as possible on the actual target cells involved in the collagen pathologies.

Automated summary

Mutations in collagen genes can cause connective tissue pathologies by affecting procollagen assembly and stability. The interaction between misfolded procollagens and cellular proteostasis machinery is closely studied to understand its relationship with the unfolded protein response (UPR) and its potential role in collagenopathies. This review examines the evidence supporting the involvement of endoplasmic reticulum stress and chronic UPR activation in the pathophysiology of collagenopathies. While there is strong evidence for the contribution of UPR in collagen X misfolding mutations, the evidence for other collagen types is incomplete. Further research is needed to understand how specific misfolding mutation types engage with the UPR and downstream signaling responses to develop targeted therapeutic approaches. It is also important to focus on the actual target cells involved in collagen pathologies to better understand the role of UPR.