The Splicing Factor hnRNP M Is a Critical Regulator of Innate Immune Gene Expression in Macrophages

West, Kelsi O; Scott, Haley M; Torres-Odio, Sylvia; West, A. Phillip; Patrick, Kristin L.; Watson, Robert O.

doi:10.1016/j.celrep.2019.09.078

Cited by 69 publications

(65 citation statements)

References 68 publications

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“…Mx1 expression was lower in all of the hnRNP as well as in SRSF1 and 7 knockdowns compared to scramble controls, except for hnRNP M (Fig. 5C), consistent with our previously characterized role for this factor in repressing Mx1 expression [35].…”

Section: Certain Innate Immune Genes Are Especially Reliant On Sr/hrnsupporting

confidence: 90%

“…We observed significant enrichment in SR/hnRNP-sensitive DEGs in pathways related to translation initiation, mTOR signaling, and phagosomal maturation ( Fig. 1D, and Table 1 for full list), which paralleled previous analyses in hnRNP M knockdown macrophages [35]. IPA of the set of 365 downregulated genes from above revealed no overlap between pathways enriched for SR/hnRNP-sensitive DEGs and those enriched for downregulated genes (Fig.…”

Section: Salmonella-infected Macrophagessupporting

confidence: 86%

“…These data led us to speculate that splicing regulatory proteins are functionalized following pathogen sensing. Consistent with this idea, we recently found that phosphorylation of one such factor-hnRNP M-at a single serine residue (S574) is sufficient to ablate its ability to repress expression of innate immune transcripts like Il6 and Mx1, suggesting that post-translational modification of this splicing factor is important to allow cells to maximally induce expression of specific innate immune genes [35]. Our studies of hnRNP M suggest that other individual RNA binding proteins may also coordinate the innate immune transcriptome in unexpected ways.…”

Section: Introductionmentioning

confidence: 71%

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Global transcriptomics reveals specialized roles for splicing regulatory proteins in the macrophage innate immune response

West

Wagner

Scott

et al. 2020

Preprint

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Pathogen sensing via pattern recognition receptors triggers massive reprogramming of macro-phage gene expression. While the signaling cascades and transcription factors that activate these responses are well-known, the role of post-transcriptional RNA processing in modulating innate immune gene expression remains understudied. Recent phosphoproteomics analyses revealed that members of the SR and hnRNP families of splicing regulatory proteins are dynamically post-translationally modified in infected macrophages. To begin to test if these splicing factors play a privileged role in controlling the innate immune transcriptome, we analyzed steady state gene expression and alternatively spliced isoform production in ten SR/hnRNP knockdown RAW 264.7 macrophage cell lines following infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (Salmonella). We identified thousands of transcripts whose abundance was increased or decreased by SR/hnRNP knockdown in macrophages. We observed that different SR/hnRNPs control the expression of distinct gene regulons in uninfected and Salmonella-infected macrophages, with several key innate immune genes (Nos2, Mx1, Il1a) relying on multiple SR/hnRNPs to maintain proper induction and/or repression. Knockdown of SR/hnRNPs promoted differential isoform usage (DIU) for a number of key immune sensors and signaling molecules and many of these splicing changes were again, distinct in uninfected and Salmonella-infected macrophages. Finally, after observing a surprising degree of similarity between the DEGs and DIUs in hnRNP K and U knockdown macrophages, we found that these cells are better able to restrict vesicular stomatitis virus replication than control cells, supporting a role for these hnRNPs in controlling infection outcomes in macrophages ex vivo. Based on these findings, we conclude that many innate immune genes have evolved to rely on one or more splicing regulatory factors to ensure the proper timing and magnitude of their induction, bolstering a model wherein pre-mRNA splicing is a critical regulatory node in the innate immune response.

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Section: Certain Innate Immune Genes Are Especially Reliant On Sr/hrnsupporting

confidence: 90%

Section: Salmonella-infected Macrophagessupporting

confidence: 86%

Section: Introductionmentioning

confidence: 71%

See 1 more Smart Citation

Global transcriptomics reveals specialized roles for splicing regulatory proteins in the macrophage innate immune response

West

Wagner

Scott

et al. 2020

Preprint

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“…Using the Immunological Genome Project transcriptional data, Ergun et al showed that over 70% of the genes expressed in immune cells undergo AS, and that exon patterns cluster according to lineage differentiation and cell cycling 36 . The type of stimuli dictates varied isoform usage in activated monocytes 37 and splicing pattern shifts in activated macrophages 38 , dendritic cells exposed to influenza 39 , and T and B lymphocytes 36 . Some genes co-expressed in B and T cells had different isoform ratios in these populations.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing of SLAMF6 in human T cells creates a co-stimulatory isoform that counteracts the inhibitory effect of the full-length receptor

Hajaj

Zisman

Tzaban

et al. 2020

Preprint

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SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor exhausted T cells. In humans, SLAMF6 has three splice isoforms involving its V-domain. While the canonical 8-exon receptor inhibits T cell activation through SAP recruitment, the short isoform SLAMF6Δ17-65 has a strong agonistic effect. The costimulatory action depends on protein phosphatase SHP-1 and leads to a cytotoxic molecular profile governed by transcription factors Tbet, Runx3, and Tcf7. In T cells from individual patients treated with immune checkpoint blockade, a shift was noted towards SLAMF6Δ17-65. Splice-switching antisense oligonucleotides designed to target the SLAMF6 splice junction, enhanced SLAMF6Δ17-65 in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The possible emergence of two opposing isoforms from the SLAMF6 gene may represent an immune-modulatory mechanism that can be exploited for cancer immunotherapy.

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“…This is an example of a direct functional consequence of cryptic exon inclusion in a TDP-43 target. Other hnRNP proteins including hnRNP C, I (PTB), L and M have also been shown to maintain splicing fidelity by repressing cryptic exons [114,130,207,217]. It remains to be confirmed whether cryptic exon repression by these hnRNPs is in any way compromised in FTLD/ALD pathogenesis.…”

Section: Hnrnps In Cryptic Splicingmentioning

confidence: 99%

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

et al. 2020

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Dysregulated RNA metabolism is emerging as a crucially important mechanism underpinning the pathogenesis of frontotemporal dementia (FTD) and the clinically, genetically and pathologically overlapping disorder of amyotrophic lateral sclerosis (ALS). Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins with diverse, multi-functional roles across all aspects of mRNA processing. The role of these proteins in neurodegeneration is far from understood. Here, we review some of the unifying mechanisms by which hnRNPs have been directly or indirectly linked with FTD/ALS pathogenesis, including their incorporation into pathological inclusions and their best-known roles in pre-mRNA splicing regulation. We also discuss the broader functionalities of hnRNPs including their roles in cryptic exon repression, stress granule assembly and in co-ordinating the DNA damage response, which are all emerging pathogenic themes in both diseases. We then present an integrated model that depicts how a broad-ranging network of pathogenic events can arise from declining levels of functional hnRNPs that are inadequately compensated for by autoregulatory means. Finally, we provide a comprehensive overview of the most functionally relevant cellular roles, in the context of FTD/ALS pathogenesis, for hnRNPs A1-U.

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The Splicing Factor hnRNP M Is a Critical Regulator of Innate Immune Gene Expression in Macrophages

Cited by 69 publications

References 68 publications

Global transcriptomics reveals specialized roles for splicing regulatory proteins in the macrophage innate immune response

Global transcriptomics reveals specialized roles for splicing regulatory proteins in the macrophage innate immune response

Alternative splicing of SLAMF6 in human T cells creates a co-stimulatory isoform that counteracts the inhibitory effect of the full-length receptor

The role of hnRNPs in frontotemporal dementia and amyotrophic lateral sclerosis

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