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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

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New publication by Molinari’s lab uncovering procollagen quality control by selective ER-phagy

on Tuesday, January 15, 2019

Maurizio Molinari’s research group, with the groups of Carmine Settembre at the Telethon Institute of Genetics and Medicine in Pozzuoli (IT) and of Ivan Dikic at the Goethe University in Frankfurt (DE), published a new work in the EMBO Journal. The study highlights the mechanisms ensuring production of collagen by our cells.

Collagens are the most abundant proteins in Metazoa, where they are major components of bones and cartilages and make up to 30% of the whole-body protein content. They are synthesized in the endoplasmic reticulum (ER), where they form triple-helixes before secretion in the extracellular space. Their very complex folding program is assisted by general, as well as collagen-specific molecular chaperones and enzymes. Nevertheless, these large polypeptide chains are prone to misfolding. Inherited or sporadic mutations in their sequence further reduce folding efficiency and are linked to rare diseases such as osteogenesis imperfecta, Ehlers-Danlos syndrome, Alport disease and many others. Solid scientific evidence is available, which shows that constitutive lysosomal clearance of defective collagen molecules maintains cellular and organ homeostasis. However, molecular mechanisms and regulation of this crucial catabolic pathway were not defined.

In this collective effort, the three research groups establish that collagen producing cells such as osteoblasts chondrosarcoma cells and fibroblasts maintain collagen production by ensuring the efficient removal from the ER of collagen molecules that fail to attain the native structure. The study shows that misfolded collagen binds a functional complex composed of the lectin chaperone calnexin and the LC3-binding protein FAM134B to be segregated in ER subdomains that are eventually captured by the autophagic machinery and are delivered to lysosomal compartments for clearance. Detailed genetic and morphometric analyses identified the ER resident factors calreticulin, ERp57, UDP-glucose:glycoprotein glucosyltransferase and the autophagy regulators FIP200, ATG7 and ATG16 as additional components of the collagen quality control machinery.

Misfolded procollagen (in red) is recognized in the ER lumen by the lectin chaperone calnexin (CANX) and the LC3-binding protein FAM134B to be segregated in ER subdomains that are eventually captured by the autophagic machinery and are delivered to lysosomal compartments (decorated by Lamp1, in green) for clearance.

This work represents another step towards the understanding of the homeostatic mechanisms that operate in mammalian cells to maintain the capacity to efficiently produce a functional proteome, a major interest of Molinari’s lab. These homeostatic mechanisms, which are defective in many rare disorders caused by protein misfolding rely on rapid recognition and destruction of faulty gene products, whose accumulation is cytotoxic and causes highly debilitating human diseases.

This work was supported by grants from Alpha-ONE Foundation, Foundation for Research on Neurodegenerative Diseases, the Novartis Foundation, Comel and Gelu Foundations, Swiss National Science Foundation (SNSF).

Article

A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex

Forrester A, De Leonibus C, Grumati P, Fasana E, Piemontese M, Staiano L, Fregno I, Raimondi A, Marazza A, Bruno G, Iavazzo M, Intartaglia D, Seczynska M, van Anken E, Conte I, De Matteis MA, Dikic I, Molinari M, Settembre C

doi: 10.15252/embj.201899847