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IPBS Seminar Series - New insights in cell autonomous immunity mechanisms

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Gloria López-Castejón

The University of Manchester, UK

How do macrophages respond to danger?

The ability to sense and respond to danger appropriately is critical for maintaining immune homeostasis. Inflammasomes are supra-molecular protein complexes that sense danger signals both from microbes and tissue damage, and initiate an inflammatory response through activation of the protease caspase-1 and subsequent release of interleukin(IL)-1β and IL-18. Dysregulation of inflammasomes contributes to the progression of chronic disease such as Alzheimer’s disease, COPD, or Rheumatoid Arthritis. In this seminar I will share our latest work on the molecular mechanisms that control inflammasome activation in macrophages, especially the contribution of the ubiquitin system to this process. 

Selected publications

  • Tapia et al. (2019) The related cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes. J Biol Chem 294(21):8325-8335
  • Green et al. (2018) Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. PNAS 115(40):E9371-E9380
  • Palazón-Riquelme et al. (2018) USP7 and USP47 deubiquitinases regulate the NLRP3 inflammasome activation. EMBO Rep 19(10). pii: e44766
  • López-Castejón et al. (2013) Deubiquitinases regulate the activity of caspase-1 and interleukin-1β secretion via assembly of the inflammasome. J Biol Chem 288(4):2721-33

 

10:40-11:20

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Caroline Goujon

IRIM, Montpellier 

Mechanisms of interferon-induced antiviral restriction

Interferons (IFNs), which are signalling proteins produced by infected cells, are among the first line of defences against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn allow the establishment of a powerful antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus. Our aim is to understand these natural defence mechanisms against pathogenic viruses by identifying new antiviral ISGs and characterizing their modes of action, with the long-term goal to inspire new therapeutic strategies.

Using a comparative transcriptomic approach in order to identify the anti-HIV-1 ISGs, we, and others, have shown that the dynamin-like MX2 (or MxB) GTPase inhibits HIV-1 nuclear import and integration (Goujon et al, Nature 2013). By screening additional ISG candidates, we have recently identified NCOA7 as an ISG inhibiting viruses entering the target cells through endocytosis, such as influenza A and hepatitis C viruses (Doyle et al, Nature Microbiology 2018). Importantly, IFN treatment induces a potent block to HIV-1 DNA accumulation and, whereas TRIM5a has recently been suggested to play a role, we believe that other cellular factors remain to be identified. Therefore, in order to identify these additional cellular effectors of the IFN-induced HIV-1 inhibition, we have developed whole-genome CRISPR-Cas9 knock-out genetic screens and successfully identified a new inhibitor. The presentation will focus on the development of the different approaches used to identify new antiviral ISGs and some of the results we have obtained.

Selected publications

  • Doyle et al. (2018) The interferon inducible isoform of NCOA7 inhibits endosome-mediated viral entry. Nat Microbiol 3(12):1369-1376
  • Doyle et al. (2015) HIV-1 and interferons: who’s interfering with whom? Nat Rev Microbiol 13(7):403-13
  • Goujon et al. (2015) A triple arginine motif in the amino-terminal domain and oligomerization are required for HIV-1 inhibition by human MX2. J Virol 89(8):4676-80
  • Goujon et al. (2014) Transfer of the amino-terminal nuclear envelope targeting domain of human MX2 converts MX1 into an HIV-1 resistance factor. J Virol 88(16):9017-26
  • Goujon et al. (2013) Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502(7472):559-62

 

11:20-12:00

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Jost Enninga

Institut Pasteur, Paris

Intracellular niche formation of bacteria pathogens

Details to be announced

Contact: Etienne Meunier (Etienne.Meunier@ipbs.fr)

Note for visitors: Please come with a valid identity card

15 Nov

10:00 - 12:00

Seminar room - IPBS - Campus 205