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Review
. 2020 Dec;11(12):881-893.
doi: 10.1007/s13238-020-00739-1. Epub 2020 Jun 16.

How are MCPIP1 and cytokines mutually regulated in cancer-related immunity?

Ruyi Xu  1   2 , Yi Li  1   2 , Yang Liu  1   2 , Jianwei Qu  1   2 , Wen Cao  1   2 , Enfan Zhang  1   2 , Jingsong He  3   4 , Zhen Cai  5   6
Affiliations
Review

How are MCPIP1 and cytokines mutually regulated in cancer-related immunity?

Ruyi Xu et al. Protein Cell. 2020 Dec.

Abstract

Cytokines are secreted by various cell types and act as critical mediators in many physiological processes, including immune response and tumor progression. Cytokines production is precisely and timely regulated by multiple mechanisms at different levels, ranging from transcriptional to post-transcriptional and posttranslational processes. Monocyte chemoattractant protein-1 induced protein 1 (MCPIP1), a potent immunosuppressive protein, was first described as a transcription factor in monocytes treated with monocyte chemoattractant protein-1 (MCP-1) and subsequently found to possess intrinsic RNase and deubiquitinase activities. MCPIP1 tightly regulates cytokines expression via various functions. Furthermore, cytokines such as interleukin 1 beta (IL-1B) and MCP-1 and inflammatory cytokines inducer lipopolysaccharide (LPS) strongly induce MCPIP1 expression. Mutually regulated MCPIP1 and cytokines form a complicated network in the tumor environment. In this review, we summarize how MCPIP1 and cytokines reciprocally interact and elucidate the effect of the network formed by these components in cancer-related immunity with aim of exploring potential clinical benefits of their mutual regulation.

Keywords: MCPIP1; RNase; cancer-related immunity; cytokines; deubiquitinase.

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Figures

Figure 1
Figure 1
Schematic structures of human MCPIP1 gene and protein. The binding sites of transcription factors Elk-1 and NF-κβ are showed in MCPIP1 gene. The location of promoter, Enhancer and Exons are also indicated in MCPIP1 gene. The protein domains are presented. UBA: ubiquitin-associated domain; RNase: ribonuclease domain
Figure 2
Figure 2
The mechanism how MCPIP1 and cytokines mutually regulated in macrophages. The upper green part indicates the mechanism how cytokines and LPS regulate MCPIP1 expression. Activation of TLR4 by LPS, or IL-1R by IL-1, subsequently activates the inhibitor of NF-κβ kinase (IKK) complex, leading to the phosphorylation and degradation of IκBα. Then NF-κβ is released and translocate to the nucleus to induce the transcription of MCPIP1 gene. MAPkinase pathway is also activated and phosphorylated Elk-1 promotes MCPIP1 transcription. Post-transcriptional regulation happened in cytoplasm, MCPIP1 mRNAs interact with miR-9 or MCPIP1 protein and undergo degradation. Those translated MCPIP1 protein can be phosphorylated by NF-κβ signaling and then degraded by proteasome machinery. The blue triangle indicates a different mechanism of MCPIP1 protein degradation in T cells. It’s mediated by protease Malt1. The Lower yellow part indicates the mechanism how MCPIP1 protein regulates cytokines production. MCPIP1 interacts with USP10 and TANK to inhibit NF-κβ signaling by deubiquitinating the activated TRAF6. In cytoplasm, MCPIP1 interacts with cytokines transcripts to induce mRNA decay. In addition, its anti-Dicer RNase activity inhibits miRNAs maturation. In nucleus, MCPIP1 directly inhibits translocated NF-κβ and AP-1 bind to the target proinflammatory cytokines genes, then suppresses proinflammatory cytokines transcription
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