High‐fat diet‐induced GAIT element‐mediated translational silencing of mRNAs encoding inflammatory proteins in macrophage protects against atherosclerosis

Basu, Abhijit; Dvorina, Nina; Baldwin, William M.; Mazumder, Barsanjit

doi:10.1096/fj.201903119r

Cited by 4 publications

(10 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, RNAi-mediated KD of RPL13a did not compromise protein synthesis activity of ribosome and survival of the KD cells 16 and secondly, Myeloid-specific Rpl13a KO mice are viable and demonstrate the physiological role of RPL13a and GAIT-element mediated translational silencing as a mechanism to control inflammation. [20][21][22][23][24][25] However, in contrast to our expectation, no Rpl13a−/− pups were born after crossing heterozygous F I G U R E 7 RNAi-mediated depletion of Rpl13a does not abrogate the expression of snoRNAs U32a, U33, and U34. (A) Expression of snoRNAs U32a, U33, and U34 harbored in the Rpl13a intronic sequence were measured by qRT-PCR (SYBR Green), the upper panel.…”

Section: Discussioncontrasting

confidence: 70%

“…Interestingly, these findings are consistent with our previous results using macrophage‐specific Rpl13a KO mice. These mice show the physiological activation of inflammatory response in the absence of RPL13a in myeloid cells 21–25 . A few studies have looked at the relationship between inflammation and pluripotency 58,59 however, myeloid cells develop from yolk sac hematopoiesis from embryonic day E8.5 which is several days after implantation 60,61 .…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19][20] Moreover, we successfully recapitulated the consequences of the depletion of RPL13a in myeloid cells in an animal model of myeloid-specific Rpl13a-KO mice without any embryonic lethality. These conditional KO animals showed severe inflammation and disease outcome compared to controls using three murine models of human diseases caused by inflammation, for example, lipopolysaccharide (LPS) induced endotoxemia, 21 high-fat diet (HFD) induced atherosclerosis, 22,23 and dextran sodium sulfate (DSS) induced colitis. 24,25 These studies motivated us to test the consequences of the systemic deletion of Rpl13a in whole animals.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of function of ribosomal protein L13a blocks blastocyst formation and reveals a potential nuclear role in gene expression

Kour,

Kim,

Roy

et al. 2023

The FASEB Journal

Self Cite

View full text Add to dashboard Cite

Ribosomal proteins play diverse roles in development and disease. Most ribosomal proteins have canonical roles in protein synthesis, while some exhibit extra‐ribosomal functions. Previous studies in our laboratory revealed that ribosomal protein L13a (RPL13a) is involved in the translational silencing of a cohort of inflammatory proteins in myeloid cells. This prompted us to investigate the role of RPL13a in embryonic development. Here we report that RPL13a is required for early development in mice. Crosses between Rpl13a+/− mice resulted in no Rpl13a−/− offspring. Closer examination revealed that Rpl13a−/− embryos were arrested at the morula stage during preimplantation development. RNA sequencing analysis of Rpl13a−/− morulae revealed widespread alterations in gene expression, including but not limited to several genes encoding proteins involved in the inflammatory response, embryogenesis, oocyte maturation, stemness, and pluripotency. Ex vivo analysis revealed that RPL13a was localized to the cytoplasm and nucleus between the two‐cell and morula stages. RNAi‐mediated depletion of RPL13a phenocopied Rpl13a−/− embryos and knockdown embryos exhibited increased expression of IL‐7 and IL‐17 and decreased expression of the lineage specifier genes Sox2, Pou5f1, and Cdx2. Lastly, a protein–protein interaction assay revealed that RPL13a is associated with chromatin, suggesting an extra ribosomal function in transcription. In summary, our data demonstrate that RPL13a is essential for the completion of preimplantation embryo development. The mechanistic basis of the absence of RPL13a‐mediated embryonic lethality will be addressed in the future through follow‐up studies on ribosome biogenesis, global protein synthesis, and identification of RPL13a target genes using chromatin immunoprecipitation and RNA‐immunoprecipitation‐based sequencing.

show abstract

Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of function of ribosomal protein L13a blocks blastocyst formation and reveals a potential nuclear role in gene expression

Kour,

Kim,

Roy

et al. 2023

The FASEB Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…This possibility is consistent with the fact that M1 macrophages prevail over M2 in AS progression. 24 Together, these scRNAseq studies provide further evidence for phenotypic heterogeneity and functional diversity of AAMs. They also provide novel insights into the roles of macrophages (particularly pro-inflammation and foam cell formation) in atherogenesis, therefore consolidating the basis for the ‘inflammation theory’ of AS.…”

Section: An Overview Of Macrophage Functions and Anti-inflammatory Th...mentioning

confidence: 87%

Targeting epigenetic modifiers to reprogramme macrophages in non-resolving inflammation-driven atherosclerosis

Jin

Guo

et al. 2021

European Heart Journal Open

View full text Add to dashboard Cite

Epigenomic and epigenetic research has been providing a number of new insights into a variety of diseases caused by nonresolving inflammation, including cardiovascular diseases. Atherosclerosis (AS) has long been recognized as a chronic inflammatory disease of the arterials walls, characterized by local persistent and stepwise accelerating inflammation without resolution, also known as uncontrolled inflammation. The pathogenesis of AS is driven primarily by highly-plastic macrophages via their polarization to pro- or anti-inflammatory phenotypes as well as other novel subtypes recently identified by single-cell sequencing. Although emgerging evidence has indicated the key role of the epigenetic machinery in the regulation of macrophage plasticity, the investigation of epigenetic alterations and modifiers in AS and related inflammation is still in its infancy. An increasing number of the epigenetic modifiers (e.g., TET2, DNMT3A, HDAC3, HDAC9, JMJD3, KDM4A) have been identified in epigenetic remodeling of macrophages through DNA methylation or histone modifications (e.g., methylation, acetylation, and recently lactylation) in inflammation. These or many unexplored modifiers function to determine or switch the direction of macrophage polarization via transcriptional reprogramming of gene expression and intracellular metabolic rewiring upon microenvironmental cues, thereby representing a promising target for anti-inflammatory therapy in AS. Here, we review up-to-date findings involving the epigenetic regulation of macrophages to shed light on the mechanism of uncontrolled inflammation during AS onset and progression. We also discuss current challenges for developing an effective and safe anti-AS therapy that targets the epigenetic modifiers, and propose a potential anti-inflammatory strategy that repolarizes macrophages from pro- to anti-inflammatory phenotypes.

show abstract

“…Thus, GAIT-mediated silencing of translation provides a feedback mechanism that effectively resolves inflammatory response ( 15 , 16 ). The physiological importance of this translational silencing mechanism as an endogenous defense mechanism against uncontrolled inflammation was illustrated by our findings that induced endotoxemia ( 17 ), colitis ( 18 , 19 ), and high-fat diet-induced atherosclerosis were all more severe in myeloid-specific L13a-knockout (KO) mice than in controls ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 98%

A Structurally Conserved RNA Element within SARS-CoV-2 ORF1a RNA and S mRNA Regulates Translation in Response to Viral S Protein-Induced Signaling in Human Lung Cells

Basu

Penumutchu

Nguyen

et al. 2022

J Virol

Self Cite

View full text Add to dashboard Cite

The positive-sense, single-stranded RNA genome SARS-CoV-2 harbors functionally important cis-acting elements governing critical aspects of viral gene expression. However, insights on how these elements sense various signals from the host cell and regulate viral protein synthesis are lacking. Here, we identified two novel cis-regulatory elements in SARS-CoV-2 ORF1a and S RNAs and describe their role in translational control of SARS-CoV-2. These elements are sequence-unrelated but form conserved hairpin structures (validated by NMR) resembling G amma A ctivated I nhibitor of T ranslation (GAIT) elements that are found in a cohort of human mRNAs directing translational suppression in myeloid cells in response to IFN-γ. Our studies show that treatment of human lung cells with receptor-binding S1 subunit, S protein pseudotyped lentivirus, and S protein-containing virus-like particles triggers a signaling pathway involving DAP-kinase1 that leads to phosphorylation and release of the ribosomal protein L13a from the large ribosomal subunit. Released L13a forms a V irus A ctivated I nhibitor of T ranslation (VAIT) complex that binds to ORF1a and S VAIT elements, causing translational silencing. Translational silencing requires extracellular S protein (and its interaction with host ACE2 receptor), but not its intracellular synthesis. RNA-protein interaction analyses and in vitro translation experiments showed that GAIT and VAIT elements do not compete with each other, highlighting differences between the two pathways. Sequence alignments of SARS-CoV-2 genomes showed a high level of conservation of VAIT elements, suggesting their functional importance. This VAIT-mediated translational control mechanism of SARS-CoV-2 may provide novel targets for small molecule intervention and/or facilitate development of more effective mRNA vaccines. Importance Specific RNA elements in the genomes of RNA viruses play important roles in host-virus interaction. For SARS-CoV-2, the mechanistic insights on how these RNA elements could sense the signals from the host cell are lacking. Here we report a novel relationship between the GAIT-like SARS-CoV-2 RNA element (called VAITs) and the signal generated from the host cell. We show that for SARS-CoV-2, the interaction of spike protein with ACE2 not only serves the purpose for viral entry into the host cell, but also transduces signals that culminate into the phosphorylation and the release of L13a from the large ribosomal subunit. We also show that this event leads to the translational arrest of ORF1a and S mRNAs in a manner dependent on the structure of the RNA elements. Translational control of viral mRNA by a host-cell generated signal triggered by viral protein is a new paradigm in the host-virus relationship.

show abstract

High‐fat diet‐induced GAIT element‐mediated translational silencing of mRNAs encoding inflammatory proteins in macrophage protects against atherosclerosis

Cited by 4 publications

References 77 publications

Loss of function of ribosomal protein L13a blocks blastocyst formation and reveals a potential nuclear role in gene expression

Loss of function of ribosomal protein L13a blocks blastocyst formation and reveals a potential nuclear role in gene expression

Targeting epigenetic modifiers to reprogramme macrophages in non-resolving inflammation-driven atherosclerosis

A Structurally Conserved RNA Element within SARS-CoV-2 ORF1a RNA and S mRNA Regulates Translation in Response to Viral S Protein-Induced Signaling in Human Lung Cells

Contact Info

Product

Resources

About