Molecular and tissue alterations of collagens in fibrosis

Ricard‐Blum, Sylvie; Baffet, Georges; Théret, Nathalie

doi:10.1016/j.matbio.2018.02.004

Cited by 127 publications

(86 citation statements)

References 360 publications

(366 reference statements)

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“…As TGF also controls gene expression involved in other biological processes than fibrosis, its inhibition can bring about many side effects, including epithelial hyperplasia, abnormal immune, and wound healing responses (56). Given the newly found role of TMEM131 in collagen secretion, inhibition of TMEM131 or its interfaces with collagen C-propeptide and TRAPPC8 may be therapeutically useful for treating pathological tissue fibrosis, including conditions in aging, systemic sclerosis, chronic inflammatory diseases, end-stage organ dysfunction, and heart failure (6,9,57,58). Realization of these therapeutic potentials will benefit from further studies on the mechanism of action, biological function, and regulation of TMEM131 family proteins in broad contexts of physiology and diseases.…”

Section: Discussionmentioning

confidence: 99%

Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking

et al. 2020

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Collagen is the most abundant protein in animals. Its dysregulation contributes to aging and many human disorders, including pathological tissue fibrosis in major organs. How premature collagen proteins in the endoplasmic reticulum (ER) assemble and route for secretion remains molecularly undefined. From an RNA interference screen, we identified an uncharacterized Caenorhabditis elegans gene tmem-131, deficiency of which impairs collagen production and activates ER stress response. We find that amino termini of human TMEM131 contain bacterial PapD chaperone–like domains, which recruit premature collagen monomers for proper assembly and secretion. Carboxy termini of TMEM131 interact with TRAPPC8, a component of the TRAPP tethering complex, to drive collagen cargo trafficking from ER to the Golgi. We provide evidence that previously undescribed roles of TMEM131 in collagen recruitment and secretion are evolutionarily conserved in C. elegans, Drosophila, and humans.

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Section: Discussionmentioning

confidence: 99%

Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking

et al. 2020

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“…As TGFß also controls gene expression involved in other biological processes than fibrosis, its inhibition can bring many side effects, including epithelial hyperplasia, abnormal immune and wound healing responses (52). Given the newly discovered role of TMEM131 in collagen secretion, inhibition of TMEM131 or its interfaces with collagen C-propeptide and TRAPPC8 may be therapeutically useful for treating pathological tissue fibrosis, including conditions in aging, systemic sclerosis, chronic inflammatory diseases, end-stage organ dysfunction and heart failure (6,9,53,54).…”

Section: Discussionmentioning

confidence: 99%

Broadly Conserved TMEM-131 Family Proteins in Collagen Production and Secretory Cargo Trafficking

Zhang

Bai

Barbosa

et al. 2019

Preprint

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Collagen is the most abundant protein in animals. Its dysregulation contributes to ageing and human disorders including tissue fibrosis in major organs. How premature collagens in the endoplasmic reticulum (ER) assemble and route for secretion remains molecularly undefined. From an RNAi screen, we identified an uncharacterized C. elegans gene tmem-131, deficiency of which impairs collagen production and activates ER stress response. TMEM-131 N-termini contain bacterial PapD chaperone-like (PapD-L) domains essential for collagen assembly and secretion. Human TMEM131 binds to COL1A2 and TRAPPC8 via N-terminal PapD-L and C-terminal domain, respectively, to drive collagen production. We provide evidence that previously undescribed roles of TMEM131 in collagen recruitment and secretion are evolutionarily conserved in C. elegans, Drosophila and humans.Collagen is the major extracellular component of connective tissues and is the most abundant protein in animals (1-3). Production of mature collagen is a multi-step process, involving collagen gene regulation, protein biosynthesis, post-translational modifications in the endoplasmic reticulum (ER), formation of secretion-competent trimers, and extracellular C-propeptide cleavage and cross-linking among trimers (1-3). Dysregulation of collagen production or deposition contributes to a wide variety of human disorders, including diabetes, ageing and pathological tissue fibrosis in major organs such as kidneys, liver, lungs and heart (4-9). The type I collagen is the most abundant fibril-type collagen and its trimer comprises two α1 (I) procollagen chains and one α2 (I) procollagen chain, encoded by the genes COL1A1 and COL1A2, respectively. Both COL1A1 and COL1A2 contain C-terminal domains (C-propeptide) responsible for initial chain trimerization. The trimerization occurs via a zipper-like mechanisms, initiating from the C-propeptide domain of α1/2 (I) in close proximity to ER membranes (10-13). Although the enzymes responsible for type I collagen modification, extracellular cleavage and cross-linking have been well described (1,14), how procollagen monomers are recruited to assemble into secretioncompetent multimers in the ER remains poorly understood.COPII-coated vesicles mediate ER-to-Golgi anterograde transport of secretioncompetent cargos, including those containing collagens (15,16). Tethering COPII vesicles from ER to Golgi membranes requires TRAPP (transport protein particle), a multi-subunit protein complex highly conserved in eukaryotes (17,18). TRAPPC8 is a key component of TRAPP III, a subtype of TRAPP that acts as a guanine nucleotide exchange factor (GEF) to activate Rab GTPase to promote ER-to-Golgi cargo trafficking. Collagen production also requires HSP47, a procollagen chaperone in the ER, and TANGO1, an ER transmembrane protein that facilitates the export of bulky cargo with collagen (19,20).Intriguingly, HSP47 and TANGO1 orthologs are present only in vertebrates (21-23), raising the question whether mechanisms conserved in all animals exist to recognize ...

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“…103 In addition to altered composition, fibrotic ECM has extensive cross-linking that makes it very difficult to degrade. 89,104 In particular, levels of hydroxyallysine cross-linking is increased, and appears to lead to irreversible collagen accumulation 105 together with other effects on cell signalling and ECM synthesis. 89…”

Section: Pathogenesis Of Fibrosismentioning

confidence: 99%

Pathological mechanisms and therapeutic outlooks for arthrofibrosis

et al. 2019

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Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury, surgery and infection. Excessive extracellular matrix and adhesions contract pouches, bursae and tendons, cause pain and prevent a normal range of joint motion, with devastating consequences for patient quality of life. Arthrofibrosis affects people of all ages, with published rates varying. The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers. However, current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis. The process begins when stress signals stimulate immune cells. The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts, which secrete fibrillar collagens and transforming growth factor-β (TGF-β). Positive feedback networks then dysregulate processes that normally terminate healing processes. We propose two subtypes of arthrofibrosis occur: active arthrofibrosis and residual arthrofibrosis. In the latter the fibrogenic processes have resolved but the joint remains stiff. The best therapeutic approach for each subtype may differ significantly. Treatment typically involves surgery, however, a pharmacological approach to correct dysregulated cell signalling could be more effective. Recent research shows that myofibroblasts are capable of reversing differentiation, and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments. Therapies with significant promise are currently available, with more in development, including those that inhibit TGF-β signalling and epigenetic modifications. This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments.

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Molecular and tissue alterations of collagens in fibrosis

Cited by 127 publications

References 360 publications

Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking

Broadly conserved roles of TMEM131 family proteins in intracellular collagen assembly and secretory cargo trafficking

Broadly Conserved TMEM-131 Family Proteins in Collagen Production and Secretory Cargo Trafficking

Pathological mechanisms and therapeutic outlooks for arthrofibrosis

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