Gian Maria Fimia

Pubblicazioni

Titolo Pubblicato in Anno
Negative regulation of MAVS-mediated antiviral signaling by the mitochondrial protein LRPPRC during HCV infection HEPATOLOGY 2018
Mycobacterium tuberculosis-induced miR-155 subverts autophagy by targeting ATG3 in human dendritic cells PLOS PATHOGENS 2018
Clinical isolates of the modern Mycobacterium tuberculosis lineage 4 evade host defense in human macrophages through eluding IL-1β-induced autophagy article CELL DEATH & DISEASE 2018
TRIM50 regulates Beclin 1 proautophagic activity BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018
Antitubercular and anti-inflammatory properties screening of natural products from Plectranthus species FUTURE MEDICINAL CHEMISTRY 2018
Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75 CELL REPORTS 2018
AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis DEVELOPMENTAL CELL 2018
TG2 regulates the heat-shock response by the post-translational modification of HSF1 EMBO REPORTS 2018
Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018 CELL DEATH AND DIFFERENTIATION 2018
Iron overload down-regulates the expression of the HIV-1 Rev cofactor eIF5A in infected T lymphocytes PROTEOME SCIENCE 2017
Methods to Study the BECN1 Interactome in the course of autophagic responses Molecular Characterization of Autophagic Responses, Part A 2017
PINK1 and BECN1 relocalize at mitochondria-associated membranes during mitophagy and promote ER-mitochondria tethering and autophagosome formation AUTOPHAGY 2017
Role of autophagy in HIV infection and pathogenesis JOURNAL OF INTERNAL MEDICINE 2017
Endoplasmic reticulum stress, unfolded protein response, and cancer cell fate FRONTIERS IN ONCOLOGY 2017
Dendritic cells activation is associated with sustained virological response to telaprevir treatment of HCV-infected patients CLINICAL IMMUNOLOGY 2017
Molecular definitions of autophagy and related processes EMBO JOURNAL 2017
Histological and proteomic profile of diabetic versus non-diabetic dilated cardiomyopathy INTERNATIONAL JOURNAL OF CARDIOLOGY 2016
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) AUTOPHAGY 2016
Hepatitis C virus relies on lipoproteins for its life cycle WORLD JOURNAL OF GASTROENTEROLOGY 2016
Overexpression of parkin rescues the defective mitochondrial phenotype and the increased apoptosis of Cockayne Syndrome A cells ONCOTARGET 2016

ERC

  • LS3_2
  • LS3_5
  • LS3_6
  • LS3_9

KET

  • Life-science technologies & biotechnologies

Interessi di ricerca

The current research projects coordinated by Prof. Fimia has dealt with the regulation of autophagy process, a main catabolic intracellular process that requires the formation of specific sequestering vesicles called autophagosomes, and the crosstalk of this process with cell proliferation, differentiation, development, cell survival and cell death, in physiological and pathological conditions.

Regulation of the autophagic response by the ubiquitin signaling.

This project is focused to the characterization of the molecular mechanisms that regulate the induction of autophagy in response to stress stimuli. To this aim, Prof. Fimia’s group has characterized the interactome of Ambra1 in normal and stress conditions using a functional proteomic approach. This analysis has allowed to define that Ambra1 interacts with the two main upstream autophagy regulators, Beclin 1 and the ULK1. This interaction is required to stimulate the activity of these proteins by mediating the binding of a series of E3 ubiquitin ligases to regulate the autophagy process including Trim32, which mediates regulative ubiquitination of autophagy proteins, and Cullin 4, which is important for the temporal regulation of the autophagic response.

Role of autophagy in antibacterial defenses of macrophages and dendritic cells.

The project aims to understand how Mycobacterium tuberculosis (MTB) is able to establish a chronic infection in macrophages and dendritic cells by evading the autophagic response. Recent studies coordinated by Prof. Fimia have shown how the fusion between autophagosomes and lysosomes is inhibited in cells infected with MTB. This inhibition is mediated by the ESX1 secretion system, one of the virulence factors of the bacterium. Importantly, autophagosome maturation is rescued when infected cells are cultured in the presence of MTB-specific T lymphocytes. These studies provided new experimental evidence of how MTB can survive within the infected cells, opening the possibility of identifying new regulatory pathways to stimulate autophagy and eliminate chronic infection.

Defining molecular mechanisms that regulates the Type I Interferon response gene expression.

In this study, we performed functional proteomic screening to better clarify the mechanisms by which HCV NS5A interacts with host proteins to subvert the interferon-mediated innate immune response and alter the autophagic process. To this end, we have created a modified version of the HCV replicon in order to purify the NS5A protein in a replication context and perform a mass spectrometric analysis of the proteins interacting with the host using experimental conditions that preserve the complexes associated with the membrane. This screening identified the LRPPRC protein as an NS5A interactor, a mitochondrial factor known to inhibit autophagy. The functional characterization of this interaction allowed us to elucidate a new antiviral response regulator and a previously uncharacterized mechanism through which NS5A inhibits activation of the IFN response after infection. The main results achieved in this study are: 1) NS5A protein localizes to the mitochondria where it binds LRPPRC; 2) the expression of LRPPRC is necessary for the inhibition of the IFN response during the infection, 3) LRPPRC directly inhibits the antiviral response by interacting with MAVS and preventing its association with TRAF3 and TRAF6. 4) LRPPRC is involved in the inhibition of autophagic response during infection, 5) NS5A is able to inhibit MAVS signaling by interacting with LRPPRC.

Role of autophagy in Oropharyngeal squamous cell carcinoma

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favorable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC

Keywords

autophagy
ubiquitin proteasome system
innate immune response
Mycobacterium tuberculosis
muscle atrophy
oropharyngeal carcinoma

Gruppi di ricerca - Responsabile

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