| Structural highlights
Disease
[ZC12A_MOUSE] Increased expression of ZC3H12A is associated with ischemic heart disease (PubMed:16574901).[1]
Function
[ZC12A_MOUSE] Bifunctional enzyme with both endoribonuclease and deubiquitinase activities involved in various biological functions such as cellular inflammatory response and immune homeostasis, glial differentiation of neuroprogenitor cells, cell death of cardiomyocytes, adipogenesis and angiogenesis. Functions as an endoribonuclease involved in mRNA decay (PubMed:26000482). Modulates the inflammatory response by promoting the degradation of a set of translationally active cytokine-induced inflammation-related mRNAs, such as IL6 and IL12B, during the early phase of inflammation (PubMed:19322177, PubMed:21115689, PubMed:23185455, PubMed:26000482). Prevents aberrant T-cell-mediated immune reaction by degradation of multiple mRNAs controlling T-cell activation, such as those encoding cytokines (IL6 and IL2), cell surface receptors (ICOS, TNFRSF4 and TNFR2) and transcription factor (REL) (PubMed:23706741). Self regulates by destabilizing its own mRNA (PubMed:22037600). Cleaves mRNA harboring a stem-loop (SL), often located in their 3'-UTRs, during the early phase of inflammation in a helicase UPF1-dependent manner (PubMed:19322177, PubMed:23185455, PubMed:23706741, PubMed:26000482, PubMed:26134560). Plays a role in the inhibition of microRNAs (miRNAs) biogenesis (By similarity). Cleaves the terminal loop of a set of precursor miRNAs (pre-miRNAs) important for the regulation of the inflammatory response leading to their degradation, and thus preventing the biosynthesis of mature miRNAs (By similarity). Plays also a role in promoting angiogenesis in response to inflammatory cytokines by inhibiting the production of antiangiogenic microRNAs via its anti-dicer RNase activity (By similarity). Functions as a deubiquitinase that affects the overall ubiquitination of cellular proteins (PubMed:21115689). Possesses deubiquitinase activity that specifically cleaves 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains on TNF receptor-associated factors (TRAFs), preventing JNK and NF-kappa-B signaling pathway activation, and hence negatively regulates macrophage-mediated inflammatory response and immune homeostasis (PubMed:21115689). Deubiquitinates also the transcription factor HIF1A, probably leading to its stabilization and nuclear import, thereby positively regulating the expression of proangiogenic HIF1A-targeted genes (By similarity). Prevents stress granules (SGs) formation and promotes macrophage apoptosis under stress conditions, including arsenite-induced oxidative stress, heat shock, and energy deprivation, which may be dependent on its deubiquitinase activity (PubMed:21971051). Plays a role in the regulation of macrophage polarization; promotes IL4-induced polarization of macrophages M1 into anti-inflammatory M2 state, depending on both endoribonuclease and deubiquitinase activities (PubMed:25934862). May also act as a transcription factor that regulates the expression of multiple genes involved in inflammatory response, angiogenesis, adipogenesis and apoptosis (PubMed:18178554, PubMed:19666473, PubMed:22739135). Functions as a positive regulator of glial differentiation of neuroprogenitor cells through an amyloid precursor protein (APP)-dependent signaling pathway (By similarity). Attenuates septic myocardial contractile dysfunction in response to lipopolysaccharide (LPS) by reducing I-kappa-B-kinase (IKK)-mediated NF-kappa-B activation, and hence myocardial proinflammatory cytokine production (PubMed:21616078).[UniProtKB:Q5D1E8][2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Regnase-1 is an RNase that directly cleaves mRNAs of inflammatory genes such as IL-6 and IL-12p40, and negatively regulates cellular inflammatory responses. Here, we report the structures of four domains of Regnase-1 from Mus musculus-the N-terminal domain (NTD), PilT N-terminus like (PIN) domain, zinc finger (ZF) domain and C-terminal domain (CTD). The PIN domain harbors the RNase catalytic center; however, it is insufficient for enzymatic activity. We found that the NTD associates with the PIN domain and significantly enhances its RNase activity. The PIN domain forms a head-to-tail oligomer and the dimer interface overlaps with the NTD binding site. Interestingly, mutations blocking PIN oligomerization had no RNase activity, indicating that both oligomerization and NTD binding are crucial for RNase activity in vitro. These results suggest that Regnase-1 RNase activity is tightly controlled by both intramolecular (NTD-PIN) and intermolecular (PIN-PIN) interactions.
Structural basis for the regulation of enzymatic activity of Regnase-1 by domain-domain interactions.,Yokogawa M, Tsushima T, Noda NN, Kumeta H, Enokizono Y, Yamashita K, Standley DM, Takeuchi O, Akira S, Inagaki F Sci Rep. 2016 Mar 1;6:22324. doi: 10.1038/srep22324. PMID:26927947[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhou L, Azfer A, Niu J, Graham S, Choudhury M, Adamski FM, Younce C, Binkley PF, Kolattukudy PE. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res. 2006 May 12;98(9):1177-85. Epub 2006 Mar 30. PMID:16574901 doi:http://dx.doi.org/10.1161/01.RES.0000220106.64661.71
- ↑ Liang J, Wang J, Azfer A, Song W, Tromp G, Kolattukudy PE, Fu M. A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages. J Biol Chem. 2008 Mar 7;283(10):6337-46. doi: 10.1074/jbc.M707861200. Epub 2008, Jan 4. PMID:18178554 doi:http://dx.doi.org/10.1074/jbc.M707861200
- ↑ Matsushita K, Takeuchi O, Standley DM, Kumagai Y, Kawagoe T, Miyake T, Satoh T, Kato H, Tsujimura T, Nakamura H, Akira S. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature. 2009 Apr 30;458(7242):1185-90. doi: 10.1038/nature07924. Epub 2009 Mar, 25. PMID:19322177 doi:http://dx.doi.org/10.1038/nature07924
- ↑ Younce CW, Azfer A, Kolattukudy PE. MCP-1 (monocyte chemotactic protein-1)-induced protein, a recently identified zinc finger protein, induces adipogenesis in 3T3-L1 pre-adipocytes without peroxisome proliferator-activated receptor gamma. J Biol Chem. 2009 Oct 2;284(40):27620-8. doi: 10.1074/jbc.M109.025320. Epub 2009 , Aug 7. PMID:19666473 doi:http://dx.doi.org/10.1074/jbc.M109.025320
- ↑ Liang J, Saad Y, Lei T, Wang J, Qi D, Yang Q, Kolattukudy PE, Fu M. MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-kappaB signaling. J Exp Med. 2010 Dec 20;207(13):2959-73. doi: 10.1084/jem.20092641. Epub 2010 Nov , 29. PMID:21115689 doi:http://dx.doi.org/10.1084/jem.20092641
- ↑ Niu J, Wang K, Graham S, Azfer A, Kolattukudy PE. MCP-1-induced protein attenuates endotoxin-induced myocardial dysfunction by suppressing cardiac NF-small ka, CyrillicB activation via inhibition of Ismall ka, CyrillicB kinase activation. J Mol Cell Cardiol. 2011 Aug;51(2):177-86. doi: 10.1016/j.yjmcc.2011.04.018. Epub, 2011 May 17. PMID:21616078 doi:http://dx.doi.org/10.1016/j.yjmcc.2011.04.018
- ↑ Qi D, Huang S, Miao R, She ZG, Quinn T, Chang Y, Liu J, Fan D, Chen YE, Fu M. Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress. J Biol Chem. 2011 Dec 2;286(48):41692-700. doi: 10.1074/jbc.M111.276006. Epub, 2011 Oct 4. PMID:21971051 doi:http://dx.doi.org/10.1074/jbc.M111.276006
- ↑ Iwasaki H, Takeuchi O, Teraguchi S, Matsushita K, Uehata T, Kuniyoshi K, Satoh T, Saitoh T, Matsushita M, Standley DM, Akira S. The IkappaB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol. 2011 Oct 30;12(12):1167-75. doi: 10.1038/ni.2137. PMID:22037600 doi:http://dx.doi.org/10.1038/ni.2137
- ↑ Younce C, Kolattukudy P. MCP-1 induced protein promotes adipogenesis via oxidative stress, endoplasmic reticulum stress and autophagy. Cell Physiol Biochem. 2012;30(2):307-20. doi: 10.1159/000339066. Epub 2012 Jun, 22. PMID:22739135 doi:http://dx.doi.org/10.1159/000339066
- ↑ Li M, Cao W, Liu H, Zhang W, Liu X, Cai Z, Guo J, Wang X, Hui Z, Zhang H, Wang J, Wang L. MCPIP1 down-regulates IL-2 expression through an ARE-independent pathway. PLoS One. 2012;7(11):e49841. doi: 10.1371/journal.pone.0049841. Epub 2012 Nov 21. PMID:23185455 doi:http://dx.doi.org/10.1371/journal.pone.0049841
- ↑ Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K, Satoh T, Mino T, Suzuki Y, Standley DM, Tsujimura T, Rakugi H, Isaka Y, Takeuchi O, Akira S. Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell. 2013 May 23;153(5):1036-49. doi: 10.1016/j.cell.2013.04.034. PMID:23706741 doi:http://dx.doi.org/10.1016/j.cell.2013.04.034
- ↑ Kapoor N, Niu J, Saad Y, Kumar S, Sirakova T, Becerra E, Li X, Kolattukudy PE. Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP. J Immunol. 2015 Jun 15;194(12):6011-23. doi: 10.4049/jimmunol.1402797. Epub 2015 , May 1. PMID:25934862 doi:http://dx.doi.org/10.4049/jimmunol.1402797
- ↑ Mino T, Murakawa Y, Fukao A, Vandenbon A, Wessels HH, Ori D, Uehata T, Tartey S, Akira S, Suzuki Y, Vinuesa CG, Ohler U, Standley DM, Landthaler M, Fujiwara T, Takeuchi O. Regnase-1 and Roquin Regulate a Common Element in Inflammatory mRNAs by Spatiotemporally Distinct Mechanisms. Cell. 2015 May 21;161(5):1058-73. doi: 10.1016/j.cell.2015.04.029. PMID:26000482 doi:http://dx.doi.org/10.1016/j.cell.2015.04.029
- ↑ Huang S, Liu S, Fu JJ, Tony Wang T, Yao X, Kumar A, Liu G, Fu M. Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation. J Biol Chem. 2015 Aug 21;290(34):20782-92. doi: 10.1074/jbc.M114.635870. Epub, 2015 Jul 1. PMID:26134560 doi:http://dx.doi.org/10.1074/jbc.M114.635870
- ↑ Yokogawa M, Tsushima T, Noda NN, Kumeta H, Enokizono Y, Yamashita K, Standley DM, Takeuchi O, Akira S, Inagaki F. Structural basis for the regulation of enzymatic activity of Regnase-1 by domain-domain interactions. Sci Rep. 2016 Mar 1;6:22324. doi: 10.1038/srep22324. PMID:26927947 doi:http://dx.doi.org/10.1038/srep22324
|
