HCFC2 is needed for IRF1- and IRF2-dependent <i>Tlr3</i> transcription and for survival during viral infections

Sun, Lei; Jiang, Zhengfan; Acosta-Rodríguez, Victoria A.; Berger, Michael; Du, Xin; Choi, Jin Huk; Wang, Jianhui; Wang, Kuan wen; Kilaru, Gokhul; Mohawk, Jennifer A.; Quan, Jia; Scott, Lindsay; Hildebrand, Sara; Li, Xiaohong; Tang, Miao; Zhan, Xiaoming; Murray, Anne R.; Vine, Diantha La; Moresco, Eva Marie Y.; Takahashi, Joseph S.; Beutler, Bruce

doi:10.1084/jem.20161630

Cited by 21 publications

(24 citation statements)

References 53 publications

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“…Furthermore, in line with the reduced metabolism of less proliferative cells, mTORC1 signaling was also found down-regulated in HCF-2 WTexpressing cells (Supplementary Figure S9). Up-regulated GSEA Hallmark sets, in addition to Interferon α and γ response consistent with the study (15) ( Supplementary Table S4), included prominent development related ones (e.g., epithelial-mesenchymal transition (EMT), myogenesis, angiogenesis, Hedgehog and Notch signaling; Figure 8D; Supplementary Figure S9B and S9C). The p53 pathway hallmark was also upregulated in HCF-2 WT , which is in line with the disturbance in cell-cycle progression.…”

Section: Elevated Hcf-2 Levels Activate Differentiation and Morphogensupporting

confidence: 72%

“…Consistent with this hypothesis, HCF-1 effectors (e.g., Set1/Ash2, Bap1, THAP11) can be found among HCF-2-associated proteins by MS analysis ( Supplementary Table S1). Additionally or alternatively, HCF-2 may have acquired its own HCF-1independent transcriptional regulatory roles and target other effector proteins, such as IRF-1 and IRF-2 as shown by Sun et al (15).…”

Section: Discussionmentioning

confidence: 99%

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HCF-2 inhibits cell proliferation and activates differentiation-gene expression programs

Gudkova

Dergai

Praz

et al. 2019

Preprint

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HCF-2 is a member of the host-cell-factor protein family, which arose in early vertebrate evolution as a result of gene duplication. Whereas its paralog, HCF-1, is known to act as a versatile chromatinassociated protein required for cell proliferation and differentiation, much less is known about HCF-2.Here, we show that HCF-2 is broadly present in human and mouse cells, and possesses activities distinct from HCF-1. Unlike HCF-1, which is excluded from nucleoli, HCF-2 is nucleolar -an activity conferred by one and a half C-terminal Fibronectin type 3 repeats and inhibited by the HCF-1 nuclear localization signal.Elevated HCF-2 synthesis in HEK-293 cells results in phenotypes reminiscent of HCF-1-depleted cells, including inhibition of cell proliferation and mitotic defects. Furthermore, increased HCF-2 levels in HEK-293 cells lead to inhibition of cell proliferation and metabolism gene-expression programs with parallel activation of differentiation and morphogenesis gene-expression programs. Thus, the HCF ancestor appears to have evolved into a small two-member protein family possessing contrasting nuclear vs. nucleolar localization, and cell proliferation and differentiation functions. transcriptional regulator called Oct-1 (reviewed by (6)). In uninfected cells, HCF-1 serves as a versatile transcriptional regulatory integrator, bringing together promoter-specific transcription factors with numerous chromatin modifiers facilitating either activation or repression of transcription (reviewed by 7). Human HCF-1 is synthesized as a large 2035-aa precursor protein, which then undergoes cleavage by O-linked-ß-N-acetylglucosamine transferase (OGT) at any of six centrally located 20-26-aa repeats called HCF-1 PRO

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Section: Elevated Hcf-2 Levels Activate Differentiation and Morphogensupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

HCF-2 inhibits cell proliferation and activates differentiation-gene expression programs

Gudkova

Dergai

Praz

et al. 2019

Preprint

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“…Peritoneal Macrophage, BMDC, and BMDM Cultures. Peritoneal macrophages were isolated as previously described (42). Mice were injected intraperitoneally with Brewer's modified thioglycolate (3% wt/vol; BD Biosciences).…”

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confidence: 99%

Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function

McAlpine

Sun

Wang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72. However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8−/− mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8−/− mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8−/− macrophages. Smcr8−/− mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand–receptor contact causes inflammatory disease in SMCR8-deficient mice.

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“…Similar to some IFN-induced genes, such as BAFF, TRIM21 and TLR3 [24][25][26], the promoter of TRIM14 contains an ISRE located from À27 to À17. Similar to some IFN-induced genes, such as BAFF, TRIM21 and TLR3 [24][25][26], the promoter of TRIM14 contains an ISRE located from À27 to À17.…”

Section: Discussionmentioning

confidence: 99%

TRIM14 expression is regulated by IRF‐1 and IRF‐2

Cui

et al. 2019

FEBS Open Bio

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Tripartite motif‐containing 14 (TRIM14) is a mitochondrial adaptor that promotes innate immune signaling and plays important roles in antiviral defense. Expression of TRIM14 is induced by interferon (IFN)‐I. However, the mechanism by which IFN‐I induces TRIM14 production is not yet determined. In this study, we have examined the function of TRIM14 promoter and found that a GC box and an IFN‐stimulated response element (ISRE) are necessary for the basal level transcription of TRIM14. We further observed that IFN‐I activates the TRIM14 promoter through the ISRE. In particular, interferon regulatory factor (IRF)‐1 and IRF‐2 bind to the TRIM14 promoter and activate transcription of TRIM14. Moreover, knockdown of IRF‐1 reduces the stimulation of TRIM14 transcription by IFN‐α, suggesting that IRF‐1 is involved in the activation of TRIM14 by IFN‐I. IRF‐2 has little effect on IFN‐α‐induced TRIM14 transcription but is essential for the basal transcription of TRIM14.

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HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections

Abstract: Sun et al. show that host cell factor C2 (HCFC2) is necessary for basal and induced Tlr3 transcription; deficiency of HCFC2 compromises survival during influenza virus and herpes simplex virus 1 infections in mice.

Cited by 21 publications

References 53 publications

HCF-2 inhibits cell proliferation and activates differentiation-gene expression programs

HCF-2 inhibits cell proliferation and activates differentiation-gene expression programs

Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function

TRIM14 expression is regulated by IRF‐1 and IRF‐2

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