RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems

Abstract

The immune system consists of two evolutionarily different but closely related responses, innate immunity and adaptive immunity. Each of these responses has characteristic receptors-Toll-like receptors (TLRs) for innate immunity and antigen-specific receptors for adaptive immunity. Here we show that the caspase recruitment domain (CARD)-containing serine/threonine kinase Rip2 (also known as RICK, CARDIAK, CCK and Ripk2) transduces signals from receptors of both immune responses. Rip2 was recruited to TLR2 signalling complexes after ligand stimulation. Moreover, cytokine production in Rip2-deficient cells was reduced on stimulation of TLRs with lipopolysaccharide, peptidoglycan and double-stranded RNA, but not with bacterial DNA, indicating that Rip2 is downstream of TLR2/3/4 but not TLR9. Rip2-deficient cells were also hyporesponsive to signalling through interleukin (IL)-1 and IL-18 receptors, and deficient for signalling through Nod proteins-molecules also implicated in the innate immune response. Furthermore, Rip2-deficient T cells showed severely reduced NF-kappaB activation, IL-2 production and proliferation on T-cell-receptor (TCR) engagement, and impaired differentiation to T-helper subtype 1 (TH1) cells, indicating that Rip2 is required for optimal TCR signalling and T-cell differentiation. Rip2 is therefore a signal transducer and integrator of signals for both the innate and adaptive immune systems.

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

“…147,148 Early studies demonstrated that RIP2-deficient mice are viable but show impaired activation of NFkB in response to TLR signalling and are more resistant to LPSinduced lethal sepsis. 149,150 However, a more recent report, using synthetic and highly purified forms of TLR ligands, contend that TLR signalling is intact in cells from RIP2 null mice, but loss of RIP2 leads to abrogation of signalling in response to stimulation of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2 by their specific ligands or the intracellular pathogen Listeria monocytogenes. 151 These findings indicate that RIP2 mediates NOD1 and NOD2 signalling but not TLR signal transduction.…”

RIP1, a kinase on the crossroads of a cell's decision to live or die

“…50 Another RIP member, RIP2, also contributes to immune responses upon TLR3 and TLR4 activation. 51 TLR3-and TLR4-induced cell death. Viral infection frequently leads to apoptosis of host cells.…”

“…76 In addition to the CARMA-Bcl10-MALT1 complex, 77 TRAF2, TRAF6 and RIP2 were also shown to be essential for TcRinduced NF-kB activation. 51,78 Recruitment of caspase-8 to FADD is competed by FLIP L , which can also bind RIP1 and TRAF2. Increased expression of c-FLIP L in T-cell lines augmented IL-2 production.…”

Identification of a TLR4‐ and TRIF‐dependent activation program of dendritic cells

“…4 demonstrate that TRIF is also required for the lipid-A-stimulated production of the intracellular proteins Pellino 1, RICK/Rip2, SOCS1, and SOCS3 that are considered to be involved in pattern recognition and cytokine receptor signaling. Whereas Pellino 1 appears to form an intermediate signaling complex with IRAK-1, IRAK-4, and TRAF6, leading to the activation of NF-‹ B [36], analysis of gene-deficient macrophages has shown that RICK/Rip2 is required for immune cell activation by Nod proteins and for optimal cytokine production in response to TLR2, TLR3, and TLR4 agonists [37,38]. SOCS1 and SOCS3 have been identified as critical negative regulators of IFN-+ and gp130 signaling, respectively [39].…”