MCPIP1 Ribonuclease Antagonizes Dicer and Terminates MicroRNA Biogenesis through Precursor MicroRNA Degradation

Abstract

MicroRNAs (miRNAs) are versatile regulators of gene expression and undergo complex maturation processes. However, the mechanism(s) stabilizing or reducing these small RNAs remains poorly understood. Here we identify mammalian immune regulator MCPIP1 (Zc3h12a) ribonuclease as a broad suppressor of miRNA activity and biogenesis, which counteracts Dicer, a central ribonuclease in miRNA processing. MCPIP1 suppresses miRNA biosynthesis via cleavage of the terminal loops of precursor miRNAs (pre-miRNAs). MCPIP1 also carries a vertebrate-specific oligomerization domain important for pre-miRNA recognition, indicating its recent evolution. Furthermore, we observed potential antagonism between MCPIP1 and Dicer function in human cancer and found a regulatory role of MCPIP1 in the signaling axis comprising miR-155 and its target c-Maf. These results collectively suggest that the balance between processing and destroying ribonucleases modulates miRNA biogenesis and potentially affects pathological miRNA dysregulation. The presence of this abortive processing machinery and diversity of MCPIP1-related genes may imply a dynamic evolutional transition of the RNA silencing system.

MCP-1-induced protein-1, an immune regulator

“…This phenomenon has also been found in other CCCH zinc-finger-containing proteins such as tristetraprolin (TTP) and Roquin (Taylor et al, 1996;Vinuesa et al, 2005;Yu et al, 2007). Recently, numerous studies have focused on the RNase activity of MCPIP1 targeting on the mRNAs of IL-6, IL-1β (Matsushita et al, 2009;Mizgalska et al, 2009), and pre-microRNAs (Suzuki et al, 2011). Another study shows that MCPIP1 can act as a deubiquitinating enzyme (DUB) targeting TNF receptor-associated factor (TRAF) family proteins (Liang et al, 2010).…”

“…The conserved element in the 3′-UTR of IL-6 mRNA and several pre-miRNAs can form hairpin structures as predicted, and MCPIP1 cleaves the pre-miRNA at the unpaired region (Suzuki et al, 2011). The recognition of a secondary structure of mRNA may be important for substrate binding and its specificity.…”

“…Recently, MCPIP1 is reported to down-regulate the expression level of several miRNAs (Suzuki et al, 2011). MCPIP1 can decrease the expression level of mature miRNA and pre-miRNA but shows no effect on pri-miRNA, indicating that MCPIP1 targets only pre-miRNAs.…”

“…MCPIP1 can decrease the expression level of mature miRNA and pre-miRNA but shows no effect on pri-miRNA, indicating that MCPIP1 targets only pre-miRNAs. The direct targets of MCPIP1 include miR-135b, miR-146a, miR-21, miR-155, miR-143, and miR-145 (Suzuki et al, 2011). Most of them have important roles in biological processes as shown in Table 1.…”

“…MCPIP1 reportedly targets the terminal loop region and cleaves miRNAs at the loop region as an endonuclease (Suzuki et al, 2011). Without the loop region, MCPIP1 fails to degrade miRNA.…”