Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.

A previously unappreciated deubiquitinase activity of MCP-induced protein 1 contributes to its role in dampening inflammatory signaling.

Activated macrophages play an important role in many inflammatory diseases. However, the molecular mechanisms controlling macrophage activation are not completely understood. Here we report that a novel CCCH-zinc finger protein family, MCPIP1, 2, 3, and 4, encoded by four genes, Zc3h12a, Zc3h12b, Zc3h12c, and Zc3h12d, respectively, regulates macrophage activation. Northern blot analysis revealed that the expression of MCPIP1 and MCPIP3 was highly induced in macrophages in response to treatment with lipopolysaccharide (LPS). Although not affecting cell surface marker expression and phagocytotic function, overexpression of MCPIP1 significantly blunted LPS-induced inflammatory cytokine and NO 2 .production as well as their gene expression. Conversely, short interfering RNA-mediated reduction in MCPIP1 augmented LPS-induced inflammatory gene expression. Further studies demonstrated that MCPIP1 did not directly affect the mRNA stability of tumor necrosis factor ␣ and monocyte chemoattractant protein 1 (MCP-1) but strongly inhibited LPS-induced tumor necrosis factor ␣ and inducible nitric-oxide synthase promoter activation. Moreover, we found that forced expression of MCPIP1 significantly inhibited LPS-induced nuclear factor-B activation. These results identify MCP-induced proteins, a novel CCCH-zinc finger protein family, as negative regulators in macrophage activation and may implicate them in host immunity and inflammatory diseases.Macrophages play an important role in many inflammatory disease states, including atherosclerosis, rheumatoid arthritis, emphysema, pulmonary fibrosis, and chronic pancreatitis. In these disease settings activated macrophages elaborate a large array of cytokines, growth factors, and proteolytic enzymes that are critical for tissue damage and repair (1). Numerous extracellular inducers of macrophage activation have been identified, among the most studied of which are lipopolysaccharide (LPS) 2 and interferon ␥ (IFN␥) (2). LPS is a structurally heterogenous material contained within the cell wall of Gram-negative bacteria and is recognized by animals as a molecule correlating to infection. It binds to Toll-like receptor 4 (TLR4), triggering multiple signaling cascades including those mediated through the transcription factor NF-B and the Janus N-terminal kinase and p38 kinase pathways (3).Much attention has focused on the pro-inflammatory signaling in activated macrophages but little is known about the mechanisms that negatively control inflammation. Understanding the molecular mechanisms involved in the inflammatory processes in macrophages is essential to the development of novel drug therapies against inflammatory diseases, including atherosclerosis.Previously, we identified a novel CCCH-zinc finger-containing protein that was significantly induced by MCP-1 in human peripheral blood monocytes and thus designated as MCP-induced protein (MCPIP) (4). By searching the similar sequences in GenBank TM , we found that four members belong to this protein family, designated as MCPIP1, 2, 3, and ...

Nearly 60 CCCH zinc finger proteins have been identified in humans and mice. These proteins are involved in the regulation of multiple steps of RNA metabolism, including mRNA splicing, polyadenylation, transportation, translation and decay. Several CCCH zinc finger proteins, such as tristetraprolin (TTP), roquin 1 and MCPIP1 (also known as regnase 1), are crucial for many aspects of immune regulation by targeting mRNAs for degradation and modulation of signalling pathways. In this Review, we focus on the emerging roles of CCCH zinc finger proteins in the regulation of immune responses through their effects on cytokine production, immune cell activation and immune homeostasis.