Protein misfolding diseases; Proteostasis; Protein folding and quality control; Endoplasmic reticulum (ER); ER-associated degradation
Rudinskiy M., Bergmann T.J., Molinari M. (2022), Quantitative and Time-Resolved Monitoring of Organelle and Protein Delivery to the Lysosome with A Tandem Fluorescent Halo-GFP reporter, in
Molecular Biology of the Cell.
Fregno Ilaria, Fasana Elisa, Soldà Tatiana, Galli Carmela, Molinari Maurizio (2021), N‐glycan processing selects ERAD‐resistant misfolded proteins for ER‐to‐lysosome‐associated degradation, in
The EMBO Journal, 40(15), e107240.
Loi Marisa, Marazza Alessandro, Molinari Maurizio (2021),
Cellular Biology of the Endoplasmic Reticulum, Springer International Publishing, Cham.
Molinari Maurizio (2021), ER-phagy responses in yeast, plants, and mammalian cells and their crosstalk with UPR and ERAD, in
Developmental Cell, 56(7), 949-966.
Klionsky Daniel J., Abdel-Aziz Amal Kamal, Abdelfatah Sara, Abdellatif Mahmoud, Abdoli Asghar, Abel Steffen, Abeliovich Hagai, Abildgaard Marie H., Abudu Yakubu Princely, Acevedo-Arozena Abraham, Adamopoulos Iannis E., Adeli Khosrow, Adolph Timon E., Adornetto Annagrazia, Aflaki Elma, Agam Galila, Agarwal Anupam, Aggarwal Bharat B., Agnello Maria, Agostinis Patrizia, Agrewala Javed N., Agrotis Alexander, Aguilar Patricia V., Ahmad S. Tariq, et al. (2021), Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1, in
Autophagy, 17(1), 1-382.
Schorr Stefan, Nguyen Duy, Haßdenteufel Sarah, Nagaraj Nagarjuna, Cavalié Adolfo, Greiner Markus, Weissgerber Petra, Loi Marisa, Paton Adrienne W., Paton James C., Molinari Maurizio, Förster Friedrich, Dudek Johanna, Lang Sven, Helms Volkhard, Zimmermann Richard (2020), Identification of signal peptide features for substrate specificity in human Sec62/Sec63‐dependent ER protein import, in
The FEBS Journal, 287(21), 4612-4640.
GuerraConcetta, MolinariMaurizio (2020), Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5, in
Cells, 9(9), 2000.
Morone Diego, Marazza Alessandro, Bergmann Timothy J., Molinari Maurizio (2020), Deep learning approach for quantification of organelles and misfolded polypeptide delivery within degradative compartments, in
Molecular Biology of the Cell, 31(14), 1512-1524.
Molinari Maurizio (2020), ER-phagy: Eating the Factory, in
Molecular Cell, 78(5), 811-813.
Marazza Alessandro, Galli Carmela, Fasana Elisa, Sgrignani Jacopo, Burda Patricie, Fassi Enrico M.A., Baumgartner Matthias, Cavalli Andrea, Molinari Maurizio (2020), Endoplasmic Reticulum and Lysosomal Quality Control of Four Nonsense Mutants of Iduronate 2-Sulfatase Linked to Hunter's Syndrome, in
DNA and Cell Biology, 39(2), 226-234.
Loi Marisa, Molinari Maurizio (2020), Mechanistic insights in recov-ER-phagy: micro-ER-phagy to recover from stress, in
Autophagy, 16(2), 385-386.
Loi Marisa, Raimondi Andrea, Morone Diego, Molinari Maurizio (2019), ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress, in
Nature Communications, 10(1), 5058-5058.
Fregno Ilaria, Molinari Maurizio (2019), Proteasomal and lysosomal clearance of faulty secretory proteins: ER-associated degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD) pathways, in
Critical Reviews in Biochemistry and Molecular Biology, 54(2), 153-163.
Volpi Vera G., Ferri Cinzia, Fregno Ilaria, Del Carro Ubaldo, Bianchi Francesca, Scapin Cristina, Pettinato Emanuela, Solda Tatiana, Feltri M. Laura, Molinari Maurizio, Wrabetz Lawrence, D’Antonio Maurizio (2019), Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice, in
PLOS Genetics, 15(4), e1008069-e1008069.
Forrester Alison, De Leonibus Chiara, Grumati Paolo, Fasana Elisa, Piemontese Marilina, Staiano Leopoldo, Fregno Ilaria, Raimondi Andrea, Marazza Alessandro, Bruno Gemma, Iavazzo Maria, Intartaglia Daniela, Seczynska Marta, Anken Eelco, Conte Ivan, De Matteis Maria Antonietta, Dikic Ivan, Molinari Maurizio, Settembre Carmine (2019), A selective ER ‐phagy exerts procollagen quality control via a Calnexin‐ FAM 134B complex, in
The EMBO Journal, 38(2), e99847.
Background and rationale-The endoplasmic reticulum (ER) is a biosynthetic organelle of eukaryotic cells. It produces lipids, oligosaccharides and about 40% of the organismal proteome. Protein biogenesis relies on assistance by molecular chaperones, folding enzymes and quality control sensors. These ensure appropriate folding of newly synthesized gene products that are subsequently transported at their intra- or extracellular site of activity. Gene mutations may affect the polypeptide capacity to attain the appropriate structure and function and may enhance the propensity to enter toxic aggregates and polymers. This is linked to an increasing number of so-called protein misfolding diseases, which are characterized by loss-of-function (e.g., on degradation of folding-defective gene products) or gain-of-function phenotypes (e.g., on aggregates or polymers deposition). Folding-defective proteins must be cleared from the ER to maintain the ER capacity to efficiently produce the proteome. Paradoxically, the ER does not contain degradation machineries. Thus, aberrant polypeptides are dislocated across the ER membrane for ER-associated degradation (ERAD) by the ubiquitin proteasome system. Alternatively, misfolded proteins that cannot be dislocated across the ER membrane, or ER subdomains that contain them, are delivered to lysosomal compartments for degradation by ER-to-lysosome-associated degradation (ERLAD) pathways that are poorly understood and whose study is not covered by this SNF allocation. Perturbation of ER homeostasis on unbalanced protein folding, quality control and/or degradation activates unfolded protein responses (UPR) aiming at rescuing or maintaining ER function. On irreversible damages, UPR trigger death programs that eliminate intoxicated cells and can eventually compromise organ homeostasis and organism health. Overall objectives and specific aims-We will characterize the mechanisms that maintain a functional ER by ensuring efficient protein folding and quality control, and dislocation across the ER membrane of misfolded proteins for proteasomal, ER-associated proteins degradation (ERAD). Methods to be used-The pathways regulating protein folding, quality control and degradation will be investigated by following the fate of disease-causing mutant polypeptides, orphan subunits of multimeric proteins, and a series of model polypeptides with specific physico/chemical features generated in our lab to differently challenge the ER (e.g., by inducing or not inducing UPR, by entering or not entering aggregates, by associating or not associating with the membrane). These polypeptides engage various folding, quality control, and ERAD pathways (e.g., by displaying or not displaying oligosaccharides, disulfide bonds, membrane anchors, ...). Expected results and impact-We will characterize the mechanisms that govern protein biogenesis and maintain ER homeostasis. We will study client-specific pathways relying on engagement of dedicated folding, quality control and clearance machineries. Our lab is also interested in elucidating receptor-mediated mechanisms of lysosomal degradation of defective ER material or of defined ER subdomains. The allocation given to our project does not allow to cover the costs of the research on these subjects. Understand protein biogenesis and quality control mechanisms and pathways in molecular details is of crucial importance because their components may be diagnostic and prognostic disease indicators and their modulation is expected to offer therapeutic opportunities in protein misfolding diseases.