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

ABSTRACT

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.

KEYWORDS:

• Collagen mutations
• unfolded protein response
• endoplasmic reticulum stress
• proteostasis
• collagenopathies
• collagen misfolding

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed here.

Notes

1. A list of commonly used abbreviations is provided in Supplementary Table 1.

2. Where collagen mutations have a legacy position number reflecting the position of the mutation within the triple helix, this is shown in parentheses eg. p.G845R (G667R). This is to help the reader correlate the discussion with the mutation nomenclature in earlier publications.

Additional information

Funding

Australian National Health & Medical Research Council (GNT1146952, GNT2003393), the Victorian Government’s Operational Infrastructure Support Program, NIH NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases R01AR071443 and a Research Grant from the G. Harold and Leila Y. Mathers Foundation; National Health and Medical Research Council [GNT1146952, GNT2003393,GNT1146952; GNT2003393];State Government of Victoria