Projets

PROJECTS ON SELECTIVE AUTOPHAGY IN INFECTION AND PATHOPHYSIOLOGY

Autophagy receptors are cytosolic proteins whose function is to lead to the degradation of unwanted intracytosolic cargos, such as pathogens, by the autophagic machinery. To target microbes towards autophagosome, autophagy receptors bind to pathogens on one hand and to LC3 on a growing autophagosomal membrane on the other hand.

Beyond their function in autophagic targeting, our team has reported an unanticipated role for several autophagy receptors (NDP52, OPTN, T6BP), which is the regulation of the maturation of bacteria-containing autophagosomes, i.e. the fusion of the autophagosome with vesicles of the endo-lysosomal pathway. To do so, we described that NDP52 binds to LC3 forms, which are found on the external autophagosomal membrane, via a new specific domain, and to endosomes via its interaction with the MYOSIN VI. Thus, in the course of anti-microbial autophagy, these autophagy receptors play a dual function, by targeting the pathogens to growing autophagosomes and then by facilitating the degradation of the bacteria sequestered within the closed autophagosome.

The project of our team is to pursue our understanding of the (dys)regulation of anti-microbial autophagy, the so-called xenophagy, by focusing on the role and the regulation of autophagy receptors in two of their functions: the targeting of pathogens towards autophagy and the regulation of autophagosome maturation. We observed an unanticipated modality of bacterial escape from xenophagy, that involves malfunctioning autophagy receptors, and we identified a new upstream regulator of autophagosome maturation; depicting these two aspects should strongly contribute to a better understanding of the defense mechanisms relying on selective autophagy during infections. We are also developing projects to analyze selective autophagy in primary human immune cells and apply our knowledge for a better understanding of Crohn’s Disease pathogenesis to which autophagy-related gene polymorphisms have been reported to be associated with.

We focus on four main axis:

– study of a new mechanism of bacterial escapement from autophagy – what should reveal a new mechanism for both autophagy escapement (by a bacteria) and exploitation (by a virus) by pathogens, what will further delineate the parameters compatible with an efficient autophagic control of intracellular pathogens in general and will increase the knowledge on autophagy regulation.

– study of the regulation of pathogen-containing autophagosome maturation – what should bring significant understanding on how autophagy receptors regulate the maturation of autophagosome, and it will tell us about the importance of theses functions in vivo.

– quantitative analyses of the autophagy flux signature of human primary cells – what will provide quantitative and qualitative informations on the autophagy status in primary human cells with a more physiological model than those used usually.

– selective autophagy in pathophysiology: study of autophagy (dys)function in ileal Crohn’ Disease – CD is a chronic intestinal inflammatory disorder affecting around 200,000 people in France and 700,000 in the US. Most affecte patients concern teenagers and young adults. Disease results in a substantially altered quality of life, an impaired work productivity and an increased mortality rate of around 30% as compared with age-matched controls. Most CD patients will undergo intestinal resection at least once, generally for a complication such as intestinal obstruction, abscess, fistula or intestinal carcinoma. Given its chronicity and the early onset of its symptoms, CD accounts for substantial costs to the health care system and society, recently estimated, in a prospective observational study, around €6000 per year and per patient.
This axis combining identification of surrogate markers, analysis of autophagic flux function/dynsfunction, well-identified autophagy variants and bacterial colonization, might help to better understand the pathophysiology of Crohn’s disease and also could help clinician making decision for using therapy capable to target autophagy (modulators as tacrolimus for instance).

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