INTRODUCTION
Cellular clearance is increasingly emerging as a fundamental process required by all cells and in all species to regulate important physiological processes, including aging and organism development. In mammals, “autophagy” represents a main and finely regulated degradative process committed to the sequestration of cellular substrates in double-membrane vesicles (or autophagosomes) that eventually fuse with the lysosome, a specialized organelle with digestive capacity (Figure 1). Proteins and entire or portions of organelles can be targeted to autophagy via receptor-mediated processes. A remarkable example is represented by “ER-phagy”, a selective receptor-mediated form of autophagy in which fragments of the endoplasmic reticulum (ER) are delivered by autophagosomes to the lysosomes for degradation (1). Notably, the ER represents the largest cellular organelle with fundamental roles, secreting one third of the human proteins. However, this process can regularly lead to the accumulation of unfolded proteins within the ER lumen, consequent to an inefficient protein folding, which triggers cellular stress, namely ER stress, and contributes to the pathogenesis of different human diseases.
Among the human disease, collagenopathies represent an example of “ER storage disorders” caused by the production of mutant collagens forming insoluble aggregates at the ER (2). Collagens represent the principal structural proteins in the extracellular matrix found in the various connective tissues, including skin, tendons, ligaments, the extracellular matrix of muscle tissue as well as cartilage and bones. Collagen is the most abundant protein in our body forming approximately from 25% to 35% of the whole-body protein content. The structural conformation of collagen is made of single amino acids forming single helices that together trimerize in a triple helix fibril at the ER (3). The properly folded collagen associate with the heat shock protein 47 (HSP47) chaperone and then leave the ER to be secreted in the extracellular matrix to form elongated fibrils in connective tissues (4). However, errors in collagen synthesis can occur and approximately 20% of newly synthesized collagen is degraded via autophagy and lysosomes as a consequence of inefficient folding or secretion (5-8) (Figure 2). Collagen plays a fundamental role on a clinical ground, as collagen molecules are currently used in treating complications of the bones and joints along with tissue regeneration and wound healing. Herein we describe in detail the ER storage diseases and the principal disorders of collagen formation, or collagenopathies, including Osteogenesis Imperfecta (OI), Ehlers-Danlos syndrome (EDS) and Spondyloepiphyseal dysplasia congenita (SEDC). We further discuss on the most recent research insights made on autophagy and on the cellular clearing processes along with the idea to tackle this process to find novel pharmacological approaches to treat ER storage disorders.
Login now to read the full article
Don’t have an account yet? Subscribe now, it’s free!
Lorem ipsum dolor sit amet, consectetur adipiscing elit, sed do eiusmod tempor incididunt.
All pubblications
archive from 2022 to today
All articles
PDF Version
Receive our latest issue alerts
directly to your mailbox
