Project

Back to overview

Protein folding, quality control and degradation in the endoplasmic reticulum

English title Protein folding, quality control and degradation in the endoplasmic reticulum
Applicant Molinari Maurizio
Number 163063
Funding scheme Project funding
Research institution Istituto di ricerca in biomedicina (IRB) Facoltà di scienze biomedice
Institution of higher education Università della Svizzera italiana - USI
Main discipline Cellular Biology, Cytology
Start/End 01.01.2016 - 31.12.2018
Approved amount 400'000.00
Show all

Keywords (8)

protein folding; folding enzymes; endoplasmic reticulum; Unfolded protein responses; N-linked oligosaccharides; protein quality control; molecular chaperones; protein degradation

Lay Summary (Italian)

Lead
Il ripiegamento e il controllo della qualità di proteine prodotte nelle nostre cellule
Lay summary

Il reticolo endoplasmatico è un organello intracellulare che controlla la produzione di proteine e lipidi. In particolare, contiene un sistema di controllo della qualità delle proteine che garantisce l’uscita di prodotti che hanno la struttura corretta e che sono in grado di funzionare in modo adeguato.

 

Difetti nella produzione delle proteine da parte del reticolo endoplasmatico causano gravi malattie come la fibrosi cistica, le malattie neurodegenerative, e tutta una serie di patologie legate al fatto che proteine difettose vengono distrutte oppure formano aggregati tossici.

 

Il nostro gruppo utilizza tecniche di biologia cellulare e molecolare per stabilire i meccanismi molecolari che stanno alla base della produzione delle proteine da parte delle cellule del nostro corpo e per capire come le cellule reagiscono alla produzione di proteine difettose.

Direct link to Lay Summary Last update: 22.01.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
A selective ER‐phagy exerts procollagen quality control via a Calnexin‐FAM134B complex
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, van Anken Eelco, Conte Ivan, De Matteis Maria Antonietta, Dikic Ivan, Molinari Maurizio, Settembre Carmine (2018), A selective ER‐phagy exerts procollagen quality control via a Calnexin‐FAM134B complex, in The EMBO Journal, e99847-e99847.
Three branches to rule them all? UPR signalling in response to chemically versus misfolded proteins-induced ER stress
Bergmann Timothy J., Molinari Maurizio (2018), Three branches to rule them all? UPR signalling in response to chemically versus misfolded proteins-induced ER stress, in Biology of the Cell, 110(9), 197-204.
ER‐to‐lysosome‐associated degradation of proteasome‐resistant ATZ polymers occurs via receptor‐mediated vesicular transport
Fregno Ilaria, Fasana Elisa, Bergmann Timothy J, Raimondi Andrea, Loi Marisa, Soldà Tatiana, Galli Carmela, D'Antuono Rocco, Morone Diego, Danieli Alberto, Paganetti Paolo, van Anken Eelco, Molinari Maurizio (2018), ER‐to‐lysosome‐associated degradation of proteasome‐resistant ATZ polymers occurs via receptor‐mediated vesicular transport, in The EMBO Journal, 37(17), e99259-e99259.
The reductase TMX1 contributes to ERAD by preferentially acting on membrane-associated folding-defective polypeptides
Guerra Concetta, Brambilla Pisoni Giorgia, Soldà Tatiana, Molinari Maurizio (2018), The reductase TMX1 contributes to ERAD by preferentially acting on membrane-associated folding-defective polypeptides, in Biochemical and Biophysical Research Communications, 503(2), 938-943.
Eat it right: ER-phagy and recovER-phagy
Loi Marisa, Fregno Ilaria, Guerra Concetta, Molinari Maurizio (2018), Eat it right: ER-phagy and recovER-phagy, in Biochemical Society Transactions, 46(3), 699-706.
Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides
Bergmann Timothy J., Fregno Ilaria, Fumagalli Fiorenza, Rinaldi Andrea, Bertoni Francesco, Boersema Paul J., Picotti Paola, Molinari Maurizio (2018), Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides, in Journal of Biological Chemistry, 293(15), 5600-5612.
Endoplasmic reticulum turnover: ER-phagy and other flavors in selective and non-selective ER clearance
Fregno Ilaria, Molinari Maurizio (2018), Endoplasmic reticulum turnover: ER-phagy and other flavors in selective and non-selective ER clearance, in F1000Research, 7, 454-454.
A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response
Fregno I., Molinari M. (2018), A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response, in F1000Prime, x.
A method for the acute and rapid degradation of endogenous proteins
Fregno I., Molinari M. (2017), A method for the acute and rapid degradation of endogenous proteins, in F1000Prime, x.
Cell-wide analysis of protein thermal unfolding reveals determinants of thermostability
Fregno I., Molinari M. (2017), Cell-wide analysis of protein thermal unfolding reveals determinants of thermostability, in F1000Prime, x.
Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy
Fregno I., Molinari M. (2017), Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy, in F1000Prime, x.
Molecular mechanism of substrate processing by the cdc48 atpase complex
Fregno I., Molinari M. (2017), Molecular mechanism of substrate processing by the cdc48 atpase complex, in F1000Prime, x.
Polyglutamine tracts regulate beclin 1-dependent autophagy
Fregno I., Molinari M. (2017), Polyglutamine tracts regulate beclin 1-dependent autophagy, in F1000Prime, x.
Reticulon 3-dependent ER-PM contact sites control EGFR nonclathrin endocytosis
Fregno I., Molinari M. (2017), Reticulon 3-dependent ER-PM contact sites control EGFR nonclathrin endocytosis, in F1000Prime, x.
Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress
Fregno I., Molinari M. (2017), Reversible protein aggregation is a protective mechanism to ensure cell cycle restart after stress, in F1000Prime, x.
STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum
Fregno I., Molinari M. (2017), STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum, in F1000Prime, x.
Role of SEC62 in ER maintenance: A link with ER stress tolerance in SEC62-overexpressing tumors?
Bergmann Timothy J., Fumagalli Fiorenza, Loi Marisa, Molinari Maurizio (2016), Role of SEC62 in ER maintenance: A link with ER stress tolerance in SEC62-overexpressing tumors?, in Molecular & Cellular Oncology, (2), e1264351-e1264351.
Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery
Fumagalli Fiorenza, Noack Julia, Bergmann Timothy J., Cebollero Eduardo, Pisoni Giorgia Brambilla, Fasana Elisa, Fregno Ilaria, Galli Carmela, Loi Marisa, Soldà Tatiana, D’Antuono Rocco, Raimondi Andrea, Jung Martin, Melnyk Armin, Schorr Stefan, Schreiber Anne, Simonelli Luca, Varani Luca, Wilson-Zbinden Caroline, Zerbe Oliver, Hofmann Kay, Peter Matthias, Quadroni Manfredo, Zimmermann Richard, et al. (2016), Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery, in Nature Cell Biology, (11), 1173-1184.
Five Questions (with their Answers) on ER-Associated DegradationEndoplasmic Reticulum-Associated Degradation
Brambilla Pisoni Giorgia, Molinari Maurizio (2016), Five Questions (with their Answers) on ER-Associated DegradationEndoplasmic Reticulum-Associated Degradation, in Traffic, 17(4), 341-350.
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
Klionsky Daniel J, Abdelmohsen Kotb, Abe Akihisa, Abedin Md Joynal, Abeliovich Hagai, Acevedo Arozena Abraham, Adachi Hiroaki, Adams Christopher M, Adams Peter D, Adeli Khosrow, Adhihetty Peter J, Adler Sharon G, Agam Galila, Agarwal Rajesh, Aghi Manish K, Agnello Maria, Agostinis Patrizia, Aguilar Patricia V, Aguirre-Ghiso Julio, Airoldi Edoardo M, Ait-Si-Ali Slimane, Akematsu Takahiko, Akporiaye Emmanuel T, Al-Rubeai Mohamed, et al. (2016), Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition), in Autophagy, 12(1), 1-222.
Post ER quality control: a role for UDP-glucose:glycoprotein glucosyl transferase and p97
Fregno Ilaria, Molinari Molinari (2016), Post ER quality control: a role for UDP-glucose:glycoprotein glucosyl transferase and p97, in Journal of Clinical Research on Rare Diseases, 40-42.

Datasets

Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Author Bergmann, Timothy J.; Fregno, Ilaria; Fumagalli, Fiorenza; Rinaldi, Andrea; Bertoni, Francesco; Boersema, Paul J.; Picotti, Paola; Molinari, Maurizio
Publication date 13.04.2018
Persistent Identifier (PID) PDX008529
Repository PRIDE archive


Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery

Author Fumagalli, Fiorenza; Noack, Julia; Bergmann, Timothy J.; Cebollero, Eduardo; Pisoni, Giorgia Brambilla; Fasana, Elisa; Fregno, Ilaria; Galli, Carmela; Loi, Marisa; Soldà, Tatiana; D’Antuono, Rocco; Raimondi, Andrea; Jung, Martin; Melnyk, Armin; Schorr, Stefan; Schreiber, Anne; Simonelli, Luca; Varani, Luca; Wilson-Zbinden, Caroline; Zerbe, Oliver; Hofmann, Kay; Peter, Matthias; Quadroni, Manfredo; Zimmermann, Richard; et al.,
Publication date 17.11.2016
Persistent Identifier (PID) PDX003961
Repository PRIDE archive


Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery

Author Fumagalli, Fiorenza; Noack, Julia; Bergmann, Timothy J.; Cebollero, Eduardo; Pisoni, Giorgia Brambilla; Fasana, Elisa; Fregno, Ilaria; Galli, Carmela; Loi, Marisa; Soldà, Tatiana; D’Antuono, Rocco; Raimondi, Andrea; Jung, Martin; Melnyk, Armin; Schorr, Stefan; Schreiber, Anne; Simonelli, Luca; Varani, Luca; Wilson-Zbinden, Caroline; Zerbe, Oliver; Hofmann, Kay; Peter, Matthias; Quadroni, Manfredo; Zimmermann, Richard; et al.,
Publication date 17.11.2016
Persistent Identifier (PID) 26881
Repository BMRB repository


Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Author Bergmann, Timothy J.; Fregno, Ilaria; Fumagalli, Fiorenza; Rinaldi, Andrea; Bertoni, Francesco; Boersema, Paul J.; Picotti, Paola; Molinari, Maurizio
Publication date 13.04.2018
Persistent Identifier (PID) GSE1083469
Repository GEO genomics data repository


Collaboration

Group / person Country
Types of collaboration
Dr. Manfredo Quadroni, UNI-Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Francesco Bertoni, IOR, Bellinzona Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Paola Picotti, ETH-Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
DDNZ Symposia “Academic Drug Discovery in Rare Diseases" Talk given at a conference Clearance of proteasome-resistant protein polymers from the endoplasmic reticulum 16.11.2018 Zurich, Switzerland Molinari Maurizio;
Spotlight on Cell Biology Talk given at a conference Mechanisms of endoplasmic reticulum turnover 26.09.2018 Bergamo, Italy Molinari Maurizio;
Alpha-1 Foundation Investigator's Meeting Talk given at a conference The role of novel ER-resident autophagy receptors in clearance of polymeric ATZ 06.09.2018 Miami, United States of America Molinari Maurizio;
Compartmental contact sites and transport processes Talk given at a conference Lysosomal clearance of proteasome-resistant protein polymers from the mammalian ER 17.06.2018 Göttingen, Germany Molinari Maurizio;
International Symposium on ER stress, glycosylation, homeostasis and diseases Talk given at a conference Clearance of proteasome-resistant protein aggregates from the endoplasmic reticulum 21.03.2018 Riken, Tokyo, Japan Molinari Maurizio;
UNI3 Individual talk Le proteine impazzite che ci fanno ammalare (parte II) 15.03.2018 Bellinzona, Switzerland Molinari Maurizio;
UNI3 Individual talk Le proteine impazzite che ci fanno ammalare (parte I) 08.03.2018 Bellinzona, Switzerland Molinari Maurizio;
Clinical Biochemical Colloquium Individual talk Protein biogenesis and protein misfolding diseases 05.03.2018 University Children's Hospital Zurich, Switzerland Molinari Maurizio;
Cellular Surveillance and Damage Response Individual talk Clearance of ERAD resistant proteins from the endoplasmic reticulum 26.02.2018 Zentrum für Molekulare Biologie der Universität Heidelberg, Germany Molinari Maurizio;
Protein Toxins: A Journey between Physiology and Medicine Talk given at a conference Life and Death of Proteins 22.02.2018 Padua, Italy Molinari Maurizio;
LS2 Annual Meeting Talk given at a conference Mammalian recovER-phagy: how does it work? 12.12.2017 Lausanne, Switzerland Loi Marisa;
TIGEM, Pozzuoli Individual talk Endoplasmic reticulum-to-lysosome-associated degradation of proteasome-resistant protein polymers 28.11.2017 Napoli, Italy Molinari Maurizio;
European Network on the Endoplasmic Reticulum, Endoplasmic Reticulum functions in physiology and patholog Talk given at a conference Clearance of protein aggregates from the endoplasmic reticulum 02.10.2017 Paris, France Molinari Maurizio;
FASEB meeting “From Unfolded Proteins in the ER to Disease” Talk given at a conference Role of ER-resident LC3-binding proteins in maintenance of ER homeostasis 18.06.2017 Saxton’s River, United States of America Molinari Maurizio;
Twelfth International Calreticulin Workshop Talk given at a conference Lysosomal-associated degradation of proteasome-resistant protein polymers from the ER 26.05.2017 Delphi, Greece Molinari Maurizio;
Incontro multidisciplinare di ricerca per clinici Individual talk Ricerca fondamentale su malattie rare: una visita in clinica 03.04.2017 Ospedale San Giovanni, Bellinzona, Switzerland Molinari Maurizio;
EMBO Meeting 2016, Structure and Function of the Endoplasmic Reticulum Talk given at a conference Translocon component Sec62 acts in endoplasmic reticulum turnover during stress recovery 23.10.2016 Girona, Spain Molinari Maurizio;
Meet the Expert Individual talk Rare Diseases: Alport’s syndrome 04.05.2016 Liceo Lugano 1, Switzerland Molinari Maurizio;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Ricerche non redditizie per l'industria dei farmaci Corriere del Ticino Italian-speaking Switzerland 2017
Media relations: print media, online media Ticino at the forefront of medical research Ticino Wellcome Italian-speaking Switzerland 2017
Media relations: print media, online media Le Proteine impazzite che ci fanno ammalare Il Caffé Italian-speaking Switzerland 2016
Other activities Presentations to high/primary school students and teachers as Commissary for Biol teaching, Ticino Italian-speaking Switzerland 2016
Media relations: print media, online media Tutte le Malattie rare ancora da sconfiggere Il Caffé Italian-speaking Switzerland 2016

Associated projects

Number Title Start Funding scheme
154421 ER-phagy mechanisms to maintain and restore endoplasmic reticulum homeostasis 01.10.2014 Sinergia
121926 Protein folding, quality control and degradation in the endoplasmic reticulum: Assessing the function of ER-resident molecular chaperones and folding factors 01.01.2009 Project funding

Abstract

Secretory, membrane-bound and organelle proteins (i.e., about 30% of the eukaryotic cell proteome) are co- or post-translationally translocated into the endoplasmic reticulum (ER). ER-resident molecular chaperones, folding, quality control and degradation factors insure maintenance of cell, tissue and organism proteostasis by catalyzing rate-limiting reactions of protein folding programs, by inspecting the final shape of newly synthesized polypeptides, by selecting for degradation terminally misfolded proteins and by allowing transport at the site of activity of native, fully assembled and functional ones.The aim of the research performed in our group is to understand how mammalian cells insure expression of the cellular proteome and how they respond to variations in ER homeostasis and in ER load with folding-defective or folding-competent polypeptides.To address these questions, we have generated plasmids and cell lines for transient, stable, inducible and tunable expression of a collection of model polypeptides. Their different topology, folding-capacity, aggregation proneness, structural features, expression levels lead to engagement of specific folding, quality control, degradation and cell adaptation pathways to be characterized in molecular details in our lab. We are in the best position to study the known pathways operating to maintain cellular proteostasis, i.e., the appropriate quality and quantity of the proteome, and to characterize new ones. The ongoing collaborations with Francesco Bertoni (Institute of Oncology Research, Bellinzona, transcriptomic), Paola Picotti (ETH-Zurich, proteomic) and Manfredo Quadroni (UNI-Lausanne, interactomic) are thought to give essential contributions to our research as detailed in the Research Plan. The results of our studies may eventually lead to the development of strategies to manipulate protein folding, quality control and degradation events. Also sought-after is the capacity to intervene to modulate cell responses to expression of mutant gene products with specific structural defects thereby contrasting progression or even cure proteopathies caused by inefficient functioning of the cellular protein factory. A better comprehension of the cellular protein factory will also improve our capacity to produce high amounts of active recombinant proteins to be employed in the clinics and in the industry.
-