on November 11, 2019
Accumulation of damaged proteins, lipid and organelles compromises cell viability and is linked to human diseases, from cancer to neurodegeneration. These aberrant materials are constantly produced by cells and their production is increased on aging, pathogen invasion and disease states. To maintain the function of tissues and organs, our cells have evolved efficient mechanisms for destruction of aberrant material that rely on two degradative devices, a macromachinery called the proteasome and a specialized organelle called the lysosome.
In a paper published this week in Nature Communication, the group of Maurizio Molinari at the IRB Bellinzona has dissected the mechanisms of cell recovery from acute stresses elicited by drugs exposure or by the accumulation of defective proteins. These mechanisms rely on fragmentation of damaged or superfluous portions of the endoplasmic reticulum, the protein factory of our cells. These portions, in the form of vesicles decorated with the membrane protein SEC62 are delivered in close proximity of lysosomes that, in pathways regulated by components of the ESCRT-III machinery, modify their membrane to engulf and destroy them.
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On resolution from an ER stress, excess and damaged ER-fragments are delivered to endolysosomes for destruction through micro-ER-phagy. ER-derived vesicles (EV) decorated with the ER-phagy receptor SEC62 (in red) are delivered to endolysosomes (EL in green, first panel) which engulf the vesicles through invagination of their limiting membrane (middle panel) releasing the vesicles inside the lumen for destruction (last panel). |
This work is part of a large project aiming at characterization of cellular components that ensure maintenance of proteostasis (i.e., the capacity to produce and deliver proteins throughout our body in appropriate quality and quantity). This will lead to identify possible diagnostic markers and therapeutic targets in human diseases (many of which are rare, inherited disorders) caused by the expression of mutated gene products.
Article
ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress.
Loi, M., A. Raimondi, D. Morone and M. Molinari
Nat Commun. 2019; 10:5058.
Maurizio Molinari is director of the laboratory Protein Folding and Quality Control at the Institute of Research in Biomedicine since the foundation of the Institute in 2000. He published more than 90 papers in high impact journals such as Science, Nature and Nature Cell Biology that have dissected in molecular details the mechanisms devised by our cells to ensure efficient production of functional proteins and the consequences for cell viability of the production of diseases-causing mutant proteins. He is Adjunct Professor at the School of Life Sciences of the Ecole Polytechnique Fédérale de Lausanne (EPFL). He is member of the Piattaforma Malattie Rare Svizzera italiana (https://www.malattierare-si.ch/) and is in the steering committee of Accelerare, a consortium of 28 partners operating in 12 Swiss academic institutions in the context of the National Rare Disease Policy aiming to use cutting-edge academic science and a unique project management structure to develop new drugs and therapies, while addressing related societal challenges (https://accelerare.ch).
