Details for: SMG8

Gene ID: 55181

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: SMG8

Ensembl ID: ENSG00000167447

Description: SMG8 nonsense mediated mRNA decay factor

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 6.34
    rCSI 7.68%
    PRS 94.86
  • cytotoxic T cell CL0000910
    CSI 2.85
    rCSI 16.36%
    PRS 98.44
  • basal cell of epidermis CL0002187
    CSI 1.8
    rCSI 3.19%
    PRS 93.02
  • suprabasal keratinocyte CL4033013
    CSI 1.55
    rCSI 2.52%
    PRS 94.72
  • melanocyte of skin CL1000458
    CSI 1.42
    rCSI 1.94%
    PRS 94.58

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
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    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [SMG8](/details-gene/55181) is a protein-coding gene located on chromosome 17q22 that encodes a key regulatory component of the nonsense-mediated mRNA decay (NMD) pathway. Functionally, it is an integral part of the SMG1 kinase complex, where it plays a critical role in regulating mRNA surveillance and the degradation of transcripts containing premature termination codons ([Link](https://pubmed.ncbi.nlm.nih.gov/19417104/), [Link](https://pubmed.ncbi.nlm.nih.gov/21245168/)). Expression data indicates that **Overall**, [SMG8](/details-gene/55181) shows particularly high significance in immune cells, especially [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203), as well as in various cell types of the epidermis, suggesting a crucial role for NMD in both long-term immune memory and skin homeostasis. ## Cellular Roles and Expression Landscape The expression profile of [SMG8](/details-gene/55181) highlights its importance in two primary biological systems: the adaptive immune system and the skin epidermis. **Overall**, the gene's most significant expression is observed in [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203) (CSI: 6.34), with notable significance also found in [cytotoxic T cell](/details-cell/CL0000910) (CSI: 2.85). This strong association with cytotoxic and memory T cell lineages suggests that the NMD pathway, regulated by [SMG8](/details-gene/55181), is a critical quality control mechanism for managing the complex transcriptional programs associated with T cell activation, differentiation, and the maintenance of long-lived memory populations. Concurrently, [SMG8](/details-gene/55181) is significantly expressed in multiple layers of the skin, including [basal cell of epidermis](/details-cell/CL0002187) (CSI: 1.80), [suprabasal keratinocyte](/details-cell/CL4033013) (CSI: 1.55), and [melanocyte of skin](/details-cell/CL1000458) (CSI: 1.42). This pattern implies a fundamental role for NMD in tissues characterized by high rates of cellular turnover, differentiation, and protein synthesis, where maintaining translational fidelity is essential for tissue integrity and function. ## Pathways and Molecular Function The primary function of [SMG8](/details-gene/55181) is centered on post-transcriptional gene regulation. It is a core participant in the **Nonsense-mediated decay (NMD)** pathway ([R-HSA-927802](https://reactome.org/content/detail/R-HSA-927802)), specifically in the branch enhanced by the exon junction complex ([R-HSA-975957](https://reactome.org/content/detail/R-HSA-975957)). This role is further defined by its involvement in the **Nuclear-transcribed mRNA catabolic process, nonsense-mediated decay** ([GO:0000184](https://www.ebi.ac.uk/QuickGO/term/GO:0000184)). At the molecular level, [SMG8](/details-gene/55181) functions through **Protein binding** ([GO:0005515](https://www.ebi.ac.uk/QuickGO/term/GO:0005515)) within the cytosol ([GO:0005829](https://www.ebi.ac.uk/QuickGO/term/GO:0005829)). Research has established that [SMG8](/details-gene/55181) and its partner, SMG9, form a subcomplex that binds to and regulates the SMG1 kinase ([Link](https://pubmed.ncbi.nlm.nih.gov/19417104/), [Link](https://pubmed.ncbi.nlm.nih.gov/20817927/)). This interaction is essential for controlling the large-scale conformational changes that activate SMG1 kinase activity during NMD, thereby fulfilling a key regulatory function ([GO:0045859](https://www.ebi.ac.uk/QuickGO/term/GO:0045859), [Link](https://pubmed.ncbi.nlm.nih.gov/21245168/)). ## Research Directions The specific expression patterns of [SMG8](/details-gene/55181) suggest key roles for NMD in specialized cellular contexts, leading to several testable hypotheses. **Proposed Hypotheses:** 1. The exceptionally high significance of [SMG8](/details-gene/55181) in memory T cells indicates that NMD is a critical mechanism for maintaining the long-term viability and functional quiescence of these cells by selectively degrading aberrant transcripts that could otherwise lead to inappropriate activation or apoptosis. 2. In the epidermis, [SMG8](/details-gene/55181)-mediated NMD may be essential for the proper execution of the keratinocyte differentiation program, ensuring the timely degradation of mRNAs specific to progenitor stages while promoting the stable expression of transcripts required for terminal differentiation and skin barrier formation. **Experimental Approach:** To test the role of [SMG8](/details-gene/55181) in memory T cell function (Hypothesis 1), a conditional knockout mouse model could be generated (e.g., *Smg8*fl/fl;CD4-Cre). Following a viral infection model such as LCMV Armstrong, the formation, maintenance, and recall response of antigen-specific memory CD8+ T cells could be compared between knockout and wild-type mice. A combination of flow cytometry to quantify T cell populations and single-cell RNA-sequencing of memory T cells would reveal defects in cell survival, differentiation, and the accumulation of aberrant transcripts in the absence of [SMG8](/details-gene/55181). **Therapeutic Potential:** As a core component of a fundamental cellular pathway, systemic targeting of [SMG8](/details-gene/55181) would likely have high toxicity. However, modulating NMD activity is an emerging therapeutic strategy. For cancers that rely on NMD to degrade anti-tumor transcripts or for genetic disorders caused by nonsense mutations, targeted inhibition of the SMG1-[SMG8](/details-gene/55181) kinase complex could be beneficial. Small molecule inhibitors designed to disrupt the [SMG8](/details-gene/55181)-SMG1 interaction, potentially delivered via cell-specific nanocarriers, could represent a future therapeutic avenue, with inhibition being the probable strategy to stabilize and restore the function of proteins truncated by premature stop codons.

Genular Protein ID: 3707635653

Symbol: SMG8_HUMAN

Name: Protein smg-8 homolog

UniProtKB Accession Codes:

Q8ND04 Q8N5U5 Q8TDN0 Q9H5P5 Q9NVQ1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 8 EMDB 13 Ensembl 3 ExpressionAtlas 1 GO 3 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 6 PDBsum 6 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 17974005

Title: The full-ORF clone resource of the German cDNA consortium.

PubMed ID: 17974005

DOI: 10.1186/1471-2164-8-399

PubMed ID: 16625196

Title: DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

PubMed ID: 16625196

DOI: 10.1038/nature04689

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 19417104

Title: SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay.

PubMed ID: 19417104

DOI: 10.1101/gad.1767209

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21245168

Title: The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8.

PubMed ID: 21245168

DOI: 10.1101/gad.606911

PubMed ID: 20817927

Title: Characterization of SMG-9, an essential component of the nonsense-mediated mRNA decay SMG1C complex.

PubMed ID: 20817927

DOI: 10.1093/nar/gkq749

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 24129315

Title: Immunoaffinity enrichment and mass spectrometry analysis of protein methylation.

PubMed ID: 24129315

DOI: 10.1074/mcp.o113.027870

PubMed ID: 33205750

Title: Regulation of RUVBL1-RUVBL2 AAA-ATPases by the nonsense-mediated mRNA decay factor DHX34, as evidenced by Cryo-EM.

PubMed ID: 33205750

DOI: 10.7554/elife.63042

PubMed ID: 33242396

Title: Recessive, deleterious variants in SMG8 expand the role of nonsense-mediated decay in developmental disorders in humans.

PubMed ID: 33242396

DOI: 10.1016/j.ajhg.2020.11.007

Sequence Information:

  • Length: 991
  • Mass: 109684
  • Checksum: 9D8168B171179CFF
  • Sequence:
    • MAGPVSLRDL LMGASAWMGS ESPGGSPTEG GGSAAGGPEP PWREDEICVV GIFGKTALRL 
NSEKFSLVNT VCDRQVFPLF RHQDPGDPGP GIRTEAGAVG EAGGAEDPGA AAGGSVRGSG 
AVAEGNRTEA GSQDYSLLQA YYSQESKVLY LLLTSICDNS QLLRACRALQ SGEAGGGLSL 
PHAEAHEFWK HQEKLQCLSL LYLFSVCHIL LLVHPTCSFD ITYDRVFRAL DGLRQKVLPL 
LKTAIKDCPV GKDWKLNCRP CPPRLLFLFQ LNGALKVEPP RNQDPAHPDK PKKHSPKRRL 
QHALEDQIYR IFRKSRVLTN QSINCLFTVP ANQAFVYIVP GSQEEDPVGM LLDQLRSHCT 
VKDPESLLVP APLSGPRRYQ VMRQHSRQQL SFHIDSSSSS SSGQLVDFTL REFLWQHVEL 
VLSKKGFDDS VGRNPQPSHF ELPTYQKWIS AASKLYEVAI DGKEEDLGSP TGELTSKILS 
SIKVLEGFLD IDTKFSENRC QKALPMAHSA YQSNLPHNYT MTVHKNQLAQ ALRVYSQHAR 
GPAFHKYAMQ LHEDCYKFWS NGHQLCEERS LTDQHCVHKF HSLPKSGEKP EADRNPPVLY 
HNSRARSTGA CNCGRKQAPR DDPFDIKAAN YDFYQLLEEK CCGKLDHINF PVFEPSTPDP 
APAKNESSPA PPDSDADKLK EKEPQTQGES TSLSLALSLG QSTDSLGTYP ADPQAGGDNP 
EVHGQVEVKT EKRPNFVDRQ ASTVEYLPGM LHSNCPKGLL PKFSSWSLVK LGPAKSYNFH 
TGLDQQGFIP GTNYLMPWDI VIRTRAEDEG DLDTNSWPAP NKAIPGKRSA VVMGRGRRRD 
DIARAFVGFE YEDSRGRRFM CSGPDKVMKV MGSGPKESAL KALNSDMPLY ILSSSQGRGL 
KPHYAQLMRL FVVVPDAPLQ IILMPQVQPG PPPCPVFYPE KQEITLPPDG LWVLRFPYAY 
VTERGPCFPP KENVQLMSYK VLRGVLKAVT Q