Cell death is increasingly recognized as an initial trigger of inflammation, and consequently also as a cause of inflammatory pathologies. Death is not the default response of most cells to innate immune receptor activation. Protective brakes, also known as molecular cell death checkpoints, are normally in place to actively repress cellular dismantlement, and thereby protect the host from its detrimental consequences. Occurrence of cell death is still observed in the context of microbial infection, where it evolved as an inflammatory backup mechanism in response to immune hijacking by microbial virulence proteins. In addition, environmental factors and/or genetic mutations can affect components of the cell death checkpoints, leading to undesired cell demise at the basis of diseases. This research project aims at characterizing a new cell death checkpoint in the TNF pathway - consisting in the detoxification of the TNFR1 cytosolic death-inducing complex by endosomal micro-autophagy - and at demonstrating its importance in the context of microbial infection and in disease. To reach this goal, we propose an integrated approach with studies performed at the biochemical, cellular and organism levels. The project is based on solid preliminary data.