An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex

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 5 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 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 protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease.

Human leukocyte antigen super-locus: nexus of genomic supergenes, SNPs, indels, transcripts, and haplotypes

“…Whereas the HLA class I and class II genomic regions encode the highly polymorphic gene complex of the HLA class I and HLA class II genes, the class III region consists of many different non-HLA genes that are involved in stress response ( HSPA1A, HSPA1B and HSPA1L ), complement cascade ( C4A, C4B, C2, CFB ), immune regulation ( NFKBIL1, FXBPL and DDX39B ), inflammation (LTA, LTB, LST1, ABCF1, AIF1, NCR3 and TNF), leukocyte maturation ( LY6G5B, LY6GSC, LY6G6D, LY6G6E and LY6G6C ), and regulation of T cell development and differentiation ( BTNL2 ) 4 , 36 . Recently, Zhou et al showed that a quartet of MHC class III genes ( NELF-E, SKIV2L, DXO and STK19 ) are involved with the metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression 37 . The class II region also contains some proteosome-processing and peptide antigen transportation non-HLA genes such as PSMB8 , PSMB9, TAP1 , and TAP2 .…”

Genomic Diversity of the Major Histocompatibility Complex in Health and Disease

“…The 18 papers gathered together in this Special Issue highlight the enormous genetic diversity and broad complexity of the MHC regulatory system and why its genomic structure and function is continuously under scientific investigation. These articles provide new insights as well as confirm some of the more tenuous and/or established beliefs about the genetic and biological roles of the MHC [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. More importantly, many of these articles point MHC researchers and scholars in new directions where technical developments and research can greatly improve our knowledge and concepts of the structure and function of the MHC genomic region, especially as functional haplotypes in humans and all the other vertebrate species on the planet that thrive or are in danger of extinction.…”

“…While three reviews of the MHC structure and function focus mostly on the MHC classical and nonclassical Class I and II genes [17,18,19], one review [20] and a research article [22] in this Special Issue specifically describe some of the genes in the MHC Class III region that are associated with the innate immune system, complement activation, inflammation and regulation of immunity [1,2,3,4]. Zhou and co-authors reviewed a cluster of four genes NELF-E, SKIV2L, DXO and STK19 (the NSDK cluster) in the human MHC Class III region that are involved in RNA metabolism and surveillance during the transcriptional and translational processes of gene expression [20]. These four genes seem to engage in the surveillance of host RNA integrity, in the destruction and turnover of faulty or expired RNA molecules or RNA viruses, and in the fine-tuning of innate immunity.…”

“…This Special Issue on the “Genomic Diversity of the MHC in Health and Disease” consists of eighteen papers with one commentary [16], five reviews [17,18,19,20,21], eleven research articles [22,23,24,25,26,27,28,29,30,31,32] and one communication [33]. These papers cover a broad range of topics on the genomic diversity of the MHC regulatory system in various vertebrate species in health and disease including structure and function; MHC Class I, II and III genes; antigen presentation; innate and adaptive immunity; neurology; transplantation; haplotypes; alleles; infectious and autoimmune diseases; fecundity; conservation; lineage; and evolution.…”

Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases

“…(A) A simplified genetic map of the human leukocyte antigen (HLA) on the short arm of chromosome 6 highlighting genes relevant to immune response and inflammation. (B) Gene copy number variations (CNVs) of the RP-C4-CYP21-TNX (RCCX) modules ( 3 , 5 , 6 ). Haplotypes with one to five RCCX modules are shown.…”