Alternative Pathways for Clearing Misfolded Proteins in Rare Diseases

Elisa Fasana, Ilaria Fregno, Carmela Galli e Tatiana Soldą e Maurizio Molinari
Elisa Fasana, Ilaria Fregno, Carmela Galli e Tatiana Soldą e Maurizio Molinari
Rare diseases like the deficiency of alpha1-antitrypsin or lysosomal storage disorders are caused by degradation of mutant proteins. In their latest study published in EMBO Reports, Elisa Fasana, Ilaria Fregno, Carmela Galli and Tatiana Soldą in the group led by Maurizio Molinari elucidate the pathways that ensure the clearance of misfolded proteins, when the major cellular clearance pathway, the ubiquitin-proteasome system, is dysfunctional.  

Bellinzona, May 23, 2024 - Proteins produced in the endoplasmic reticulum (ER) of our cells are assisted by molecular chaperones and are offered a given time to complete their folding program. If folding fails or is too slow as it happens in mutant proteins linked to rare "protein misfolding diseases", the polypeptide chain is degraded. It is important to establish the mechanisms regulating protein degradation from the ER because their inhibition prolongs the time available to nascent polypeptides to attain the native structure thus increasing the fraction of functional proteins produced by the cells. On the contrary, their enhancement facilitates removal of misfolded or aged polypeptides that would otherwise accumulate in our cells. Normally, misfolded proteins are exported from the ER into the cytoplasm, where they are poly-ubiquitylated and degraded by 26S-proteasomes in catabolic processes collectively defined as ER-associated degradation (ERAD).

Our team examined the fate of misfolded proteins in cells with dysfunctional ERAD upon pharmacologic inactivation of sugar processing enzymes that determine the time allocated to polypeptides to attain the native structure, upon inhibition of 26S-proteasomes, or upon elimination of various ERAD regulators by CRISPR-Cas9 genome editing. Our experiments show that ERAD dysfunction is compensated by the activation of alternative pathways that regulate segregation of misfolded polypeptides in ER subdomains. These eventually deliver their content to lysosomal compartments for clearance by mechanisms that we have named ER-to-lysosome-associated degradation (ERLAD). ERLAD involves luminal molecular chaperones like calnexin, ER-phagy receptors like FAM134B and autophagy gene products like LC3.