Posts Tagged ‘prevents’

Human antibody protects unborn mice from Zika

Researchers have identified a human antibody that prevents Zika from infecting the fetus and damaging […]

The post Human antibody protects unborn mice from Zika appeared first on Futurity.

RIPK1 inhibits ZBP1-driven necroptosis during development.

Receptor interacting protein kinase 1 (RIPK1) promotes cell survival—mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis1,2,3. However, mice expressing catalytically inactive RIPK1 are viable2,4,5, so an ill-defined pro-survival function for the RIPK1 scaffold has been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also called DAI) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice expressing mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis6, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3 D161N, RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses7,8 but previously had no role during development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIM Mlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIM Ripk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.

RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammation via kinase-dependent and -independent functions1, 2, 3, 4, 5, 6, 7. RIPK1 kinase activity induces caspase-8-dependent apoptosis and RIPK3/mixed lineage kinase like (MLKL)-dependent necroptosis8, 9, 10, 11, 12, 13. In addition, RIPK1 inhibits apoptosis and necroptosis via kinase-independent functions, which are important for late embryonic development and the prevention of inflammation in epithelial barriers14, 15, 16, 17, 18. The mechanism by which RIPK1 counteracts RIPK3/MLKL-mediated necroptosis has remained enigmatic. Here we show that RIPK1 prevents skin inflammation by inhibiting Z-DNA binding protein 1 (ZBP1, also named DAI or DLM1)-mediated activation of RIPK3/MLKL-dependent necroptosis. ZBP1 deficiency inhibited keratinocyte necroptosis and skin inflammation in mice with epidermis-specific RIPK1 knockout. Moreover, mutation of the conserved RIP homotypic interaction motif (RHIM) of endogenous mouse RIPK1 (RIPK1mRHIM) caused perinatal lethality that was prevented by RIPK3, MLKL or ZBP1 deficiency. Furthermore, mice expressing only RIPK1mRHIM in keratinocytes developed skin inflammation that was abrogated by MLKL or ZBP1 deficiency. Mechanistically, ZBP1 interacted strongly with phosphorylated RIPK3 in cells expressing RIPK1mRHIM, suggesting that the RIPK1 RHIM prevents ZBP1 from binding and activating RIPK3. Collectively, these results show that RIPK1 prevents perinatal death as well as skin inflammation in adult mice by inhibiting ZBP1-induced necroptosis. Furthermore, these findings identify ZBP1 as a critical mediator of inflammation beyond its previously known role in antiviral defence and suggest that ZBP1 might be implicated in the pathogenesis of necroptosis-associated inflammatory diseases.

Niwrad: The cancer of Darwinism

Our valued contributor Niwrad send in this post, on recent claims that cancer disproves ID: — Evolutionism is systematic negation of reality and inversion of truth. So we must be prepared to listen to ever more unbelievable things from evolutionists. Here I will examine an example that seems particularly meaningful. Cancer has universally been considered […]

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