Pellino proteins: novel players in TLR and IL-1R signalling

Abstract

Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family play important roles in immunity and inflammation. They initiate common intracellular signalling cascades leading to the activation of nuclear factor-?B (NF-?B) and other transcription factors that stimulate the expression of a variety of genes that shape an appropriate immune response. TLR/IL-1R signalling involves multiple proteinprotein interactions, but the mechanisms that regulate these interactions are still largely unclear. In this context, Pellino proteins have been suggested to function as evolutionary conserved scaffold proteins in TLR/IL-1R signalling. However, recently Pellino proteins were also proposed to function as novel ubiquitin ligases for IL-1R associated kinase 1 (IRAK-1). Here we review our current knowledge on the expression, biological role and mechanism of action of Pellino proteins in TLR/IL-1R-induced signalling.

1

Schematic overview of LPS-induced MyD88-dependent signalling leading to IKK and MAPK activation. Upon LPS-binding (mediated by MD-2 and CD14) to TLR4 and subsequent TLR4 clustering, Mal, MyD88, IRAK-1, Tollip and IRAK-4 are recruited to the cytoplasmic part of the receptor via TLR4/MyD88 TIR–TIR interactions (1). IRAK-4 phosphorylates IRAK-1 (2), leading to IRAK-1 activity and autophosphorylation (3). Tollip is also phosphorylated by IRAK-1 and leaves the receptor complex (Complex I) (4). IRAK-1 interacts with TRAF6 and the TRAF6 adaptor protein TIFA (5). IRAK-1/TRAF6/TIFA leave the receptor complex (6) and associate with the preformed (but inactive) TAK1/TAB1/TAB2 complex (7), resulting in the formation of Complex II. There, TAK1 and TAB1 are phosphorylated after which TRAF6/TAK1/TAB1/TAB2 migrate back to the cytosol (8), while IRAK-1 remains at the membrane and is most likely degraded by the proteasome (9). TIFA promotes the oligomerization and activation of TRAF6, leading to TRAF6 K63-linked polyubiquitination and subsequent TAK1 activation (10). TAK1 is then responsible for the downstream activation of IKK as well as MAPK pathways (11). Pellino proteins associate with IRAK-1, TRAF6 and TAK1 in Complex II and III, and become phosphorylated by IRAK-1 (12). Pellino-1 and -2 also induce IRAK-1 polyubiquitination (13). DD = Death Domain, KD = active kinase domain, KD*= inactive kinase domain, RING = RING domain, FHA = Forkhead Associated domain, Ub = Ubiquitin, Zf = Zinc-finger, TRAF = TRAF domain and P = phosphorylation. For more information, see text.

2

Schematic alignment of some representative Pellino proteins. Different exons of a particular Pellino are marked in a different colour, and homologous exons in various Pellino sequences are indicated in the same colour. The RING-like domain in the C-terminal part of every Pellino is boxed in red. (h) = human; (d) =Drosophila. For more information, see text.

3

Alignment of the mammalian Pellino-RING (CHC2CHC2) consensus sequence with the C3HC4 RING consensus sequence, which was adopted from [37].