Utrecht University (logo) (logo)
Universitair Medisch Centrum Utrecht (logo)

Coming up

You are here: Home > Research > Research groups > UMC Utrecht > Reggiori

F. (Fulvio) Reggiori, PhD

Monday 23 September 2013

Autophagy and Infections
Autophagy is a catabolic transport route conserved among all eukaryotes and it is required for the rapid degradation of large portions of the cytoplasm, protein aggregates, excess or damaged organelles and invading pathogens. It has long been known that this pathway is essential to generate an internal pool of nutrients that allows cells surviving starvation periods. Recent studies, however, have revealed that autophagy participates in a multitude of other cellular processes including cell differentiation and development, degradation of aberrant structures, lifespan extension, type II programmed cell death, innate and adaptive immunity. As a result, this pathway plays a relevant role in the pathophysiology of neurodegenerative, cardiovascular, chronic inflammatory, muscular and autoimmune diseases, and some malignancies. Conversely, a deficiency in this protective transport route leads to illnesses such as sporadic breast, ovarian and prostate cancers, and cardiomyophaties.

The basic mechanism of autophagy is the sequestration of the cargo that has to be degraded by autophagosomes. These large double-membrane vesicles are formed by expansion and sealing of a small cisterna known as the phagophore or isolation membrane. Once complete, they first fuse with endosomes to form amphisomes and then with lysosomes to deliver their cargo into the hydrolytic interior of this compartment for degradation. The central actors of this highly regulated pathway are the autophagy (Atg) proteins, which mediate the formation of the phagophore and its expansion into an autophagosome. Upon induction of autophagy, Atg proteins associate to form the so-called phagophore assembly site (PAS) or pre-autophagosomal structure, the precursor structure of the phagophore. Despite the identification of the Atg proteins, the molecular mechanism that directs formation of the sequestering vesicles remains largely unknown.

While part of the laboratory is working on the mechanism and regulation of autophagy, the long-term objective of our research is to understand the contribution of autophagy in medically relevant physiological and pathological situations in humans. We have recently started to investigate coronavirus (CoVs) infections and the interrelationship of these viruses with the autophagy machinery in partnership with the laboratory of Xander de Haan (Virology Division, Utrecht University, the Netherlands) and that of Maurizio Molinari (Institute of Biomedical Research, Bellinzona, Switzerland). CoV are positive-stranded RNA viruses, the relevance of which has considerably increased due to the recent emerging of the SARS-CoV. Once inside the host cell, they induce the formation of double-membrane vesicles (DMVs) on the surface of which they anchor their RNA transcription/replication complexes. These DMVs resemble autophagosomes and it has been suggested that genes involved in autophagy could play a role in DMV formation. Using the mouse hepatitis virus (MHV) as a model for the CoV infection cycle, we have found that MHV-induced DMVs are associated with the non-lipidated form of LC3/Atg8, a protein involved in autophagy. Although LC3 depletion blocks DMV formation and severely impairs MHV replication, the autophagy machinery is not required for MHV infection. The ER-associated degradation (ERAD) tuning mediates the rapid turnover of chaperones such as EDEM1 and OS-9 by transporting them to the lysosome through vesicles also coated with non-lipidated LC3. We have discovered that during MHV infection, EDEM1 and OS-9 are inside the DMVs and fail to be degraded. Our data have revealed the cellular pathway hijacked by CoV, e.g. the ERAD tuning, and this discovery has opened new therapeutic avenue for the treatment of infections caused by this family of viruses. We are currently trying to identify the MHV proteins that induce DMVs formation and determine with which ERAD tuning components they interact by using biochemical and cell biological approaches.

Our study on the interaction between autophagy and CoV was one of the first revealing that Atg proteins, individually or as a functional cluster, can be part of other cellular pathways. We have recently embarked in a series of investigations exploiting members of different virus families to uncover other unconventional functions of Atg proteins, in particular in immune responses.

Key publications
1. Bestebroer J, V’kovski P, Mauthe M, Reggiori F (2013), Hidden behind autophagy: The unconventional roles of the ATG proteins, Traffic, 14, 1029–1041.
2. Boya P, Reggiori F*, Codogno P (2013), Autophagy: Recycling and beyond, Nat Cell Biol, 15, 713-720
3. Rieter E, Vinke F, Bakula D, Cebollero E, Ungermann C, Proikas-Cezanne T, Reggiori F (2013), Atg18 function in autophagy is regulated by specific sites within its β-propeller, J Cell Sci, 126, 593-604.
4. Monastyrska I, Ulasli M, Rottier PJM, Reggiori F*, de Haan CAM (2013), An autophagy-independent role for LC3 in equine arteritis virus replication, Autophagy, 9, 164-74.
Cebollero E, van der Vaart A, Zhao M, Rieter E, Klionsky DJ, J. Helms B, Reggiori F (2012), Phosphatidylinositol-3-phosphate clearance plays a key role in autophagosome completion, Curr Biol, 22, 1545-1553.
Bernasconi R, Galli C, Noack J, Bianchi S, de Haan C, Reggiori F, Molinari M (2012), SEL1L:LC3-I complex as an ERAD tuning receptor in the mammalian ER, Mol Cell, 46, 809-19.

5. Nair U, Jotwani A, Geng J, Gammoh N, Richerson D, Yen W-L, Griffith J, Nag S, Wang K, Moss T, Baba M, McNew JA, Jiang X, Reggiori F*, Melia TJ, Klionsky DJ (2011), SNARE proteins are required for macroautophagy, Cell, 146, 290-302.
6. Mari M, Griffith J, Rieter E, Krishnappa L, Klionsky DJ, Reggiori F (2010), An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis, J Cell Biol, 190, 1005-1022.
7. Van der Vaart A, Griffith J, Reggiori F (2010), Exit from the Golgi is required for the expansion of the autophagosomal phagophore in the yeast Saccharomyces cerevisiae, Mol Biol Cell, 21, 2270–2284.
8. Reggiori F*, Monastyrska I, Verheije MH, Calì’ T, Ulasli M, Bianchi S, Bernasconi R, de Haan CAM, Molinari M (2010), Coronaviruses hijack LC3-I-positive EDEMosome membranes for replication, Cell Host Microbe, 7, 500-508.
9. Ulasli M, Verheije MH, de Haan CAM, Reggiori F (2010), Qualitative and quantitative ultrastructural analysis of the membrane rearrangements induced by coronavirus, Cell Microbiol, 12, 844-861.
*co-corresponding author

Post docsPhD students
Muriel MariSusana Abreu*
Mario MautheAndri Fraenkl*
Jana Sanchez-WanderlmerRodrigo Soares Guimaraes*
*Not a member of the I & I PhD programme