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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

New paper from the Molinari lab

on Monday, January 13, 2020

In a recent paper published in DNA and Cell Biology, the group of Maurizio Molinari from the IRB demonstrated that misfolded proteins passing ER quality control are subjected to a second structural check-point within lysosomes. Only polypeptides that pass both quality control triages will eventually mature in their functional conformation and fulfil their activity within our cells. This finding adds modulation of as-yet poorly characterized lysosomal quality control pathways to the list of possible therapeutic targets to contrasts rare lysosomal storage disorders.

Mutant proteins are often prone to misfolding and are not transported at their intra- or extra-cellular site of activity. Rather, they are retained in the endoplasmic reticulum (ER), the site of production of all secretory and membrane-bound proteins and of proteins destined to the cellular organelles, including the lysosome. In the ER, all gene products are subjected to a stringent quality control that retains and/or destroys misfolded ones, thus resulting in loss-of-function diseases. As such, processes occurring within the ER are strong candidates for therapeutic intervention.

Motivated by a case study, a child affected by Hunter’s syndrome, Molinari’s group engaged in a collaboration with the group of Andrea Cavalli (IRB, expert in molecular dynamics) and with the group of Matthias Baumgartner (Division of Metabolic Diseases, Children's Hospital Zurich - Eleonore Foundation). Hunter’s syndrome is a rare X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. IDS is one of the sulfatase enzymes required for lysosomal degradation of glycosaminoglycans. Aim of the study, was to compare the intracellular fate of the full-length form of IDS (IDSWT) and of four nonsense mutations (IDSL482X, IDSY452X, IDSR443X, and IDSW337X) generating progressively shorter forms of IDS associated with mild to severe forms of the disease. The study revealed that all forms of IDS were formylated at cysteine 84, which is a prerequisite for enzymatic activity. The shortest form of IDS, IDSW337X, was retained upon quality control inspection in the ER and was immediately degraded by the ubiquitin-proteasome system. All other forms of IDS passed ER quality control and were transported to the lysosomes. However, in contrast to the full-length protein, which was processed in the active form of the enzyme, the truncated, disease-causing forms of the protein alerted lysosomal quality control, resulting in their rapid clearance and in the loss-of-function phenotype. ER quality control (the double-check of protein fitness within the biosynthetic compartment that captures and degrades IDSW337X) is well-studied. The data reveal that passing ER quality control may not be sufficient for a protein to eventually fulfill its biological role. Rather, lysosomes emerge as distal site of a poorly studied protein quality control check-point, whose activity could be modulated to preserve or re-gain activity of faulty gene products. Lysosomal quality control could thus be the site of additional therapeutic interventions.



Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome.

Marazza, A., C. Galli, E. Fasana, J. Sgrignani, P. Burda, E. M. A. Fassi, M. Baumgartner, A. Cavalli and M. Molinari

DNA Cell Biol. 2020; doi: 10.1089/dna.2019.5221.