unfolded protein response and its relevance to connective tissue diseases

• Published in: Cell and tissue research Vol. 339; no. 1; pp. 197 - 211
• Main Authors: Boot-Handford, Raymond P, Briggs, Michael D
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.01.2010; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Activating Transcription Factor 6 - biosynthesis; Activating Transcription Factor 6 - genetics; Animals; Apoptosis; Apoptosis - genetics; Biomedical and Life Sciences; Biomedicine; Cellular biology; Chondrocytes - metabolism; Chondrocytes - pathology; Connective Tissue Diseases - genetics; Connective Tissue Diseases - metabolism; Connective Tissue Diseases - pathology; Control systems; eIF-2 Kinase - biosynthesis; eIF-2 Kinase - genetics; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Endoribonucleases - biosynthesis; Endoribonucleases - genetics; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Gene Expression Regulation - genetics; Gene mutations; Homeostasis - genetics; Human Genetics; Humans; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Molecular Medicine; Mutation; Osteoblasts - metabolism; Osteoblasts - pathology; Protein folding; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Proteins; Proteomics; Quality control; Review; Tissues; Unfolded Protein Response; Cartilage; Connective tissue diseases; Chondrodysplasia; Endoplasmic reticulum stress; Unfolded protein response
• ISSN: 0302-766X; 1432-0878
• DOI: 10.1007/s00441-009-0877-8

The unfolded protein response (UPR) has evolved to counter the stresses that occur in the endoplasmic reticulum (ER) as a result of misfolded proteins. This sophisticated quality control system attempts to restore homeostasis through the action of a number of different pathways that are coordinated in the first instance by the ER stress-senor proteins IRE1, ATF6 and PERK. However, prolonged ER-stress-related UPR can have detrimental effects on cell function and, in the longer term, may induce apoptosis. Connective tissue cells such as fibroblasts, osteoblasts and chondrocytes synthesise and secrete large quantities of proteins and mutations in many of these gene products give rise to heritable disorders of connective tissues. Until recently, these mutant gene products were thought to exert their effect through the assembly of a defective extracellular matrix that ultimately disrupted tissue structure and function. However, it is now becoming clear that ER stress and UPR, because of the expression of a mutant gene product, is not only a feature of, but may be a key mediator in the initiation and progression of a whole range of different connective tissue diseases. This review focuses on ER stress and the UPR that characterises an increasing number of connective tissue diseases and highlights novel therapeutic opportunities that may arise.