Oral Presentation Lorne Infection and Immunity 2019

Mechanisms for suppressing pro-inflammatory cell death during development (#25)

Kim Newton 1
  1. Genentech, South San Francisco, CA, United States

The kinase RIPK1 acts downstream of TNF receptor 1 to nucleate a death-inducing complex that can activate caspase-8 or the related kinase RIPK3 to kill cells.  Depending on the substrates available to it, caspase-8 can trigger either apoptosis or pyroptosis, whereas caspase-8 inhibition activates RIPK3- and MLKL-dependent necroptosis.  Cell death is an important immune defense mechanism against infection, but the lytic forms of cell death may also exacerbate inflammatory disease.  Consequently, there is considerable interest in the therapeutic potential of RIPK1 inhibitors that prevent RIPK1 autophosphorylation and subsequent assembly of the death-inducing complex.  Although activation of caspase-8 and RIPK1 can promote cell death, genetic studies indicate that these proteins are critical brakes on cell death and inflammation during development.  I will present experiments that seek to unveil the mechanistic details of their pro-survival functions.