Endonuclease Regnase‐1/Monocyte chemotactic protein‐1‐induced protein‐1 (MCPIP1) in controlling immune responses and beyond

Abstract

The activation of inflammatory cells is controlled at transcriptional and posttranscriptional levels. Posttranscriptional regulation modifies mRNA stability and translation, allowing for elaborate control of proteins required for inflammation, such as proinflammatory cytokines, prostaglandin synthases, cell surface co-stimulatory molecules, and even transcriptional modifiers. Such regulation is important for coordinating the initiation and resolution of inflammation, and is mediated by a set of RNA-binding proteins (RBPs), including Regnase-1, Roquin, Tristetraprolin (TTP), and AU-rich elements/poly(U)-binding/degradation factor 1 (AUF1). Among these, Regnase-1, also known as Zc3h12a and Monocyte chemotactic protein-1-induced protein-1 (MCPIP1), acts as an endoribonuclease responsible for the degradation of mRNAs involved in inflammatory responses. Conversely, the RBPs Roquin and TTP trigger exonucleolytic degradation of mRNAs by recruiting the CCR4-NOT deadenylase complex. Regnase-1 specifically recognizes stem-loop structures present in 3 0 -untranslated regions of cytokine mRNAs, and directly degrades the mRNAs in a translation-and ATP-dependent RNA helicase upframeshift 1 (UPF1)-dependent manner that is reminiscent of nonsense-mediated decay. Regnase-1 regulates the activation of innate and acquired immune cells, and is critical for maintaining immune homeostasis as well as preventing over-activation of the immune system under inflammatory conditions. Furthermore, recent studies have revealed that Regnase-1 and its family members are involved not only in immunity but also in various biological processes. In this article, I review molecular mechanisms of Regnase-1-mediated mRNA decay and its physiological roles.

UPFront and center in RNA decay: UPF1 in nonsense-mediated mRNA decay and beyond

“…mRNAs harboring a CDE are selectively recognized and rapidly degraded by the ring finger-and CCCH-type domain-containing protein known as roquin (Leppek et al 2013). Recent studies revealed that 3 ′ UTR CDEs are also recognized by the zinc finger CCCH-type containing 12a protein known as regnase 1 (also known as ZC3H12A, and originally identified as monocyte chemotactic protein-induced protein 1; Mino et al 2015;Takeuchi 2018). Regnase 1 contains a PilT amino-terminal (PIN)-like RNase domain (also called a NYN domain) that manifests endoribonuclease activity (Matsushita et al 2009).…”

Post‐transcriptional control of immune responses and its potential application

“…In a similar fashion, a set of immune‐related RBPs harbor CCCH‐type zinc finger domains . Key examples of such RBPs include members of the ZFP36 family, Roquin‐1,2 and Regnase family (ZC3H12A‐D, MCPIP1‐4 or Regnase‐1‐4) …”

“…14 Key examples of such RBPs include members of the ZFP36 family, 15 Roquin-1,2 16 and Regnase family (ZC3H12A-D, MCPIP1-4 or Regnase-1-4). 17 TTP recognises AREs in the 3 0 UTR of target mRNAs via its two zinc finger domains and destabilises them by recruiting the carbon catabolite repression 4negative on TATA-less (CCR4-NOT) deadenylation complex via an evolutionarily conserved C-terminal motif. 18 TTP deficiency in mice leads to autoimmune symptoms, with cachexia and arthritis resulting from excess TNF production.…”

RNA binding proteins in the control of autoimmune diseases

“…This process, initiated by endoribonucleases including Regnase-1, generates bare 5 0 and 3 0 ends, which are targeted by the above-mentioned exonucleolytic enzymes. [33]. In addition, other RBPs which lack this domain have also shown to be involved in the regulation of immune reactions.…”