Gian Maria Fimia


Titolo Pubblicato in Anno
The interplay between SARS-CoV-2 infected airway epithelium and immune cells modulates regulatory/inflammatory signals ISCIENCE 2022
Transglutaminase 2 regulates innate immunity by modulating the STING/TBK1/IRF3 axis JOURNAL OF IMMUNOLOGY 2021
Transglutaminase type 2 regulates the Wnt/β-catenin pathway in vertebrates CELL DEATH & DISEASE 2021
Autophagy in major human diseases EMBO JOURNAL 2021
High Levels of TRIM5α Are Associated with Xenophagy in HIV-1-Infected Long-Term Nonprogressors CELLS 2021
The unbalanced p53/SIRT1 axis may impact lymphocyte homeostasis in COVID-19 patients INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES 2021
Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection ANTIVIRAL RESEARCH 2021
Pharmacological modulators of autophagy as a potential strategy for the treatment of covid-19 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 2021
AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability AUTOPHAGY 2021
Multi-omics approach to COVID-19: a domain-based literature review JOURNAL OF TRANSLATIONAL MEDICINE 2021
Melanoma secretion of transforming growth factor-β2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration BRITISH JOURNAL OF DERMATOLOGY 2021
TRIM proteins in autophagy: selective sensors in cell damage and innate immune responses CELL DEATH AND DIFFERENTIATION 2020
Inhibition of Transglutaminase 2 as a Potential Host-Directed Therapy Against Mycobacterium tuberculosis FRONTIERS IN IMMUNOLOGY 2020
Mitochondrial Interactome: A Focus on Antiviral Signaling Pathways FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 2020
Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 2020
Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress CELLS 2020
Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19) CELL DEATH AND DIFFERENTIATION 2020
Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs AUTOPHAGY 2020
HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1 AUTOPHAGY 2020
On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2 CELL DEATH & DISEASE 2020


  • LS3_2
  • LS3_5
  • LS3_6
  • LS3_9


  • 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


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

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