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An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex

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An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex cells Review An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex Danlei Zhou 1,2,3,* , Michalea Lai 2,3, Aiqin Luo 1,* and Chack-Yung Yu 2,3,* 1 School of Life Science, Beijing Institute of Technology, Beijing 100081, China 2 The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA 3 Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA * Correspondence: [email protected] (D.Z.); [email protected] (A.L.); [email protected] (C.-Y.Y.) Received: 19 July 2019; Accepted: 29 August 2019; Published: 30 August 2019 Abstract: At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 50 triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3 5 through the Ski-exosome 0! 0 complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5 caps and destruction of faulty adducts in 5 3 fashion; and (d) STK19 on nuclear 0 0! 0 protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease. Keywords: DXO; DOM3Z; NELF-E; RD; SKIV2L; SKI2W; STK19; RP1; NSDK; RLR; miR1236; SVA; RNA quality control; 5 3 RNA decay; 3 5 mRNA turnover; antiviral immunity; interferon β; 0! 0 0! 0 promoter-proximal transcriptional pause; exosomes; nuclear kinase; hepatocellular carcinoma; Ski complex; trichohepatoenteric syndrome; melanoma 1. Introduction In 1984, Professor Rodney Porter’s team in Oxford reported the cloning and confirmed the physical linkage of the genes for human complement C4A and C4B, factor B and C2 through overlapping cosmids [1]. These genes are located at the central region of the human major histocompatibility complex (MHC), a region that is associated with numerous complex autoimmune Cells 2019, 8, 1008; doi:10.3390/cells8091008 www.mdpi.com/journal/cells CellsCells 20192019, 8, ,x8 ,FOR 1008 PEER REVIEW 2 of2 of 22 22 C3 convertases. The complement system is a major effector arm for both innate and adaptive immune systemsdiseases [8] [.2 While–7]. They C2 and code factor for the B essential are only constituents separated by of thean intergenic classical, lectin distance and alternativeof 421 bp [ pathways9], it was a bit C3puzzling convertases. that the The genes complement for C4 systemand factor is a major B are e ffseparatedector arm by for a both large innate gap andof 30 adaptive kb. Thus, immune it was satisfyingsystems when [8]. While a genomic C2 and DNA factor probe B are onlyupstream separated of the by C4 an promoter intergenic region distance successfully of 421 bp [ 9fished], it was out an a1.1 bit kb puzzling cDNA thatclone the that genes was for dubbed C4 and factoras RPB (to are memorialize separated by the a large lategap Professor of 30 kb. Rodney Thus, itPorter was ) satisfying when a genomic DNA probe upstream of the C4 promoter region successfully fished out an [10,11]. Working from the other end, Meo’s team reported the cloning of RD that is up to 149 bp tail- 1.1 kb cDNA clone that was dubbed as RP (to memorialize the late Professor Rodney Porter) [10,11]. to-tail with factor B [12]. The protein sequence of RD is fascinating because of its 23 consecutive copies Working from the other end, Meo’s team reported the cloning of RD that is up to 149 bp tail-to-tail with of positively charged arginine (R) and negatively charged aspartic acid (D), not to mention its leucine factor B [12]. The protein sequence of RD is fascinating because of its 23 consecutive copies of positively zipper and RNA binding motif. Between RD and RP, we found two more genes, SKI2W and DOM3Z charged arginine (R) and negatively charged aspartic acid (D), not to mention its leucine zipper and [13RNA–15]. binding motif. Between RD and RP, we found two more genes, SKI2W and DOM3Z [13–15]. ThroughThrough biochemical biochemical and and molecular molecular biologic biologic research research to decipherdecipher theirtheir functions,functions, these these four four “novel“novel”” genes genes turn turn out out to to be be extremely extremely old old in in evolution evolution.. Except for RP,RP, structurallystructurally and and functionally functionally relatedrelated genes genes and and proteins proteins can can be traced allall the the way way back back to to yeast yeast or metazoans.or metazoans. The The modern modern names names for forthese these four four genes genes are areN ELF-E,NELF-ESKIV2L,, SKIV2L,DXO DXO and and STK ST19K (NSDK),19 (NSDK) respectively., respectively. Unlike Unlike the Class the IClass and I andClass Class II andII and complement complement that that have have distinct distinct immunologic immunologic functions functions involving involving proteins, proteins NSDK seems, NSDK seemsto play to play fundamental fundamental life functions life functions in eukaryotes in eukaryotes and actively and actively engaged engaged in the surveillancein the surveillance of RNA of RNAintegrity integrity including including the the 50 cap 5′ cap and and 30 tail.3′ tail. In In the the process process of of cell cell metabolism, metabolism, these these four four genes genes play play criticalcritical roles roles on on transcription transcriptionalal control, control, RNA RNA turnover turnover and signaling.signaling. TheyThey maymay also also fine-tune fine-tune the the innateinnate immune immune response response or or type type I Iinterferon interferon-mediated-mediated inflammation inflammation elicitedelicited byby infections infections of of RNA RNA viruses.viruses. Here Here we we give give a brief a brief account account on on the the molecular molecular genetics genetics and biologybiology of of this this RNA RNA metabolism metabolism andand surveillance surveillance “quarte “quartet”t” in in the the MHC MHC (Figure (Figure 1,). Table 1). (A) Figure 1. Cont. Cells 2019, 8, x FOR PEER REVIEW 3 of 22 Cells 2019, 8, 1008 3 of 22 NELFE / RD SKIV2L / SK2W DXO /DOM3Z STK19 / RP1 (B) FigureFigure 1. Map and genegene structuresstructures of of the the NSDK NSDK (NELF-E, (NELF-E, SKIV2L, SKIV2L, DOX DOX and and STK19) STK19) quartet quartet in the in the majormajor histocompatibility complexcomplex (MHC) (MHC complement) complement gene gene cluster. cluster. (A )(A ) molecular A molecular map map comparing comparing thethe gene gene organization ofof human human and and mouse mouse MHC MHC complement complement gene gene cluster cluster with with RNA RNA surveillance surveillance quartequartett consisting ofof NELF-E,NELF-E, SKIV2L, SKIV2L, DXO DXO and and STK19 STK19 at at the the intergenic intergenic region region between between complement complement factorfactor B andand complementcomplement C4A C4A gene. gene. Original Original gene gene names names are are shown shown as alternatives.as alternatives. The The mouse mouse sequencessequences with identitiesidentities fromfrom 50–100% 50–100% are are plotted plotted below below the the human human sequences. sequences. Exons Exons for humanfor human genesgenes are shown asas solid,solid, purplepurple boxes. boxes. The The genomic genomic region region spanned spanned for for each each gene gene is shaded is shaded green. green. TheThe 5 5’’ and 3’3’ untranslateduntranslated sequences sequences are are in in yellow yellow boxes. boxes. The The conserved conserved coding coding sequences sequences between between human and mouse genes are highlighted in purple. Locations of CpG rich dinucleotides are shown as human and mouse genes are highlighted in purple. Locations of CpG rich dinucleotides are shown orange boxes. Large, repetitive retroelements SVA and endogenous retrovirus HERV-K(C4) are shown as orange boxes. Large, repetitive retroelements SVA and endogenous retrovirus HERV-K(C4) are in burgundy. Arrows with solid lines represent configurations of structural genes. RP2 and TNXA shown in burgundy. Arrows with solid lines represent configurations of structural genes. RP2 and are partially duplicated gene fragments. CYP21A is a pseudogene in human. Pseudogenes
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