RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition

Abstract

Significance The protein kinase receptor interacting protein 1 controls signaling via death receptors, Toll-like receptors, and retinoic acid-inducible gene 1-like receptors, dictating inflammatory outcomes as broad as cytokine activation and cell death. RIP1 makes a vital contribution during development, evident from the fact that RIP1-deficient mice die soon after birth. Here, we show that a kinase-independent function of RIP1 dampens the consequences of innate immune cell death. During parturition, RIP1 prevents the lethal consequences of RIP3-dependent necroptosis as well as caspase 8 (Casp8)-dependent apoptosis. In contrast to the RIP1-deficient phenotype, mice lacking a combination of RIP1, RIP3, and Casp8 are born and mature into viable, fertile, and immunocompetent adults. These results demonstrate the important protective role of RIP1 against physiologic and microbial death cues encountered at birth.

RIP kinases: key decision makers in cell death and innate immunity

“…75 This may, at least partly, underlie the perinatal lethality associated with RIP1 deficiency but would require that any such protective effects of RIP1 are independent of kinase activity as RIP1 kinase dead knockin mice survive to adulthood. 63,76,77 In addition, during development the physiological role of RIP1 in regulating RIP3-driven necroptosis appears to be highly dependent on the stage of development with RIP1 being required for TNF-induced necroptosis at E10.5 78 but inhibiting necroptosis and associated inflammation at later stages of development. 78,79 Although RIP3-driven necroptosis contributes to the perinatal defects associated with RIP1 deficiency, it is not the sole underlying mechanism.…”

“…63 This is supported by recent studies demonstrating an important role for RIP1 in protecting against TNF-and caspase 8-driven apoptosis. 76,79 Under conditions of TNF stimulation, or during virus infection, that trigger RIP1-dependent necrosis, RIP3 promotes necrosis-specific phosphorylation of RIP1, thus forming a pro-necrotic necrosome complex. 62 Phosphorylation-induced activation of the necrosome is dependent on prior de-ubiquitination of RIP1 by CYLD, a step that is proposed to take place in the necrosome itself and not in Complex I.…”

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

“…5 Besides the kinase activity, RIPK1 appears to have a scaffolding function, which may influence immune homeostasis. 6,7 Depending on the interacting partners and posttranslational modifications, RIPK1 has a multifaceted role in cell signaling and cell survival. 8 Following TNF-R1 signaling, RIPK1 transitions between pro-survival and pro-cell death signaling complexes.…”

“…5 Besides the kinase activity, RIPK1 appears to have a scaffolding function, which may influence immune homeostasis. 6,7 Depending on the interacting partners and posttranslational modifications, RIPK1 has a multifaceted role in cell signaling and cell survival.8 Following TNF-R1 signaling, RIPK1 transitions between pro-survival and pro-cell death signaling complexes. 9,10 Necroptosis is a form of regulated necrosis of cells that operates in the absence of caspase activity 9 and is initiated by the engagement of various TLRs or cytokine receptors.…”

Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

“…[5][6][7][8][9][10] Inactive RIPK1 functions to inhibit RIPK3 activation, even under conditions in which RIPK3 is activated independently of RIPK1. [11][12][13] These complex interactions help to account for the lethal effects of ablating FADD, caspase-8 or RIPK1. 14 MLKL is a substrate for RIPK3 kinase activity [1][2][3] and appears to execute the process of necroptosis by targeting the plasma membrane.…”