Structure and Function of an Effector Domain in Antiviral Factors and Tumor Suppressors SAMD9 and SAMD9L
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PROVIDER: PRJNA773935 | ENA |
REPOSITORIES: ENA
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Project description:SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and myeloid tumor suppressors. They are critical for innate immune defense against several viruses, particularly the poxviruses. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multi-domain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L associated human diseases.
2022-01-19 | GSE186456 | GEO
Project description:SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multidomain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases.
| S-EPMC8795524 | biostudies-literature
Project description:As a defense strategy against viruses or competitors, some microbes employ anticodon nucleases (ACNases) to deplete essential tRNAs, effectively halting global protein synthesis. However, this mechanism has not been observed in multicellular eukaryotes. Here, we report that human SAMD9 is an ACNase that specifically cleaves phenylalanine tRNA (tRNAPhe), resulting in codon-specific ribosomal pausing and stress signaling. While SAMD9 ACNase activity is normally latent in cells, it can be activated by poxvirus infection or rendered constitutively active by SAMD9 mutations associated with various human disorders, revealing tRNAPhe depletion as an antiviral mechanism and a pathogenic condition in SAMD9 disorders. We identified the N-terminal effector domain of SAMD9 as the ACNase, with substrate specificity primarily determined by a eukaryotic tRNAPhe-specific 2’-O-methylation at the wobble position, making virtually all eukaryotic tRNAPhe susceptible to SAMD9 cleavage. Notably, the structure and substrate specificity of SAMD9 ACNase differ from known microbial ACNases, suggesting convergent evolution of a common immune defense strategy targeting tRNAs.
2023-06-07 | GSE229979 | GEO
Project description:Transfer RNAs (tRNAs) are one of the most conserved components of protein synthesis machinery. An effective strategy for microbes to defend against viruses or competitors is to employ anticodon nucleases (ACNases) to deplete essential tRNAs and thereby shut off global protein synthesis, but this strategy has not been observed in multicellular eukaryotes. Here, we report that human SAMD9 is a virus-activatable ACNase that specifically depletes phenylalanine tRNA (tRNAPhe), causing codon-specific ribosomal pausing and inducing stress signaling. SAMD9 ACNase can be activated by poxvirus infection or by SAMD9 mutations associated with a spectrum of developmental or immunological disorders, implicating tRNAPhe deficiency as a major toxic effect in these human diseases and suggesting a new therapeutic strategy. The specificity of the ACNase, located to an N-terminal effector domain of SAMD9, is largely determined by a eukaryotic tRNAPhe specific 2’-O-methylation at the wobble position, making eukaryotic tRNAPhe a universal but specific target for SAMD9. The SAMD9 ACNase differs from the microbial ACNases in structure and substrate specificity, suggesting convergent evolution resulted in a universal immune defense strategy targeting tRNAs.
2023-06-07 | GSE230043 | GEO
Project description:The goal of this study is to use RNA-sequencing to profile the transcriptional changes in A549 cells with SAMD9 overexpression by plasmid transfection. Specifically, we were interested in determining the interferons and chemokines induced by SAMD9 overexpression. We observed that each of the type III interferons and several pro-inflammatory cytokines such as CCL5 and CXCL10 were among the top induced genes following SAMD9 overexpression.
2024-12-31 | GSE228684 | GEO
Project description:Recently, heterozygous germline mutations were identified in sterile alpha motif (SAM) domain-9 (SAMD9) and its paralog, SAMD9-like (SAMD9L) in children with monosomy 7 mediated MDS. Expression of SAMD9 and SAMD9L is induced by interferons and other inflammatory stimuli and causes reduced cell division and cell growth and most pathogenic mutations found in patients dramatically enhance these effects. The goal of this project is to identify the interactome of SAMD9 and SAMD9L to better understand their role in cell cycle and proliferation regulation
2021-03-24 | PXD020018 | Pride
Project description:Innate triggering and antiviral effector functions of activin A
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Project description:Here, we used a lentiviral over-expression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling and functional validation, we found that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, protein translation, and proliferation of HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a toxic cellular environment that promotes DNA-damage repair defects and ultimately lead to apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.
2020-11-30 | GSE152420 | GEO
Project description:hiPSC were derived from fibroblasts of two patients carrying a heterozygous mutation in the SAMD9 gene. The patients have a multisystem disorder of intrauterine growth restriction (IUGR) with gonadal, adrenal and bone marrow failure and high mortality. To examine a potential influence of the SAMD9 mutation on cell differentiation hiPSC were differentiated towards intermediate mesoderm, from which can further differentiate to adrenal gland in normal human development. Gene expression profiles of undifferentiated and differentiated cells were analysed and compared to iPSC lines derived from normal donors.
2017-06-02 | E-MTAB-5145 | biostudies-arrayexpress
Project description:Effect of Arid1a deletion in antiviral effector CD8+ T cells. [RNA-seq]
| PRJNA945945 | ENA