HIPK2 is necessary for type I interferon–mediated antiviral immunity

Cao, Lili; Yang, Guang; Gao, Shandian; Jing, Chunxia; Montgomery, Ruth R.; Yin, Yuxin; Wang, Penghua; Fikrig, Erol; You, Fangtian

doi:10.1126/scisignal.aau4604

Cited by 19 publications

(20 citation statements)

References 58 publications

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“…The present study used BMDMs to analyze the expression levels of HIPK2 in in vitro inhibitor experiments and in in vitro experiments with HIPK2 interference, while PMs were used to ensure the interference efficacy ( 4 ). The results were in accordance with a previous study that reported that HIPK2 was crucial in maintaining type I interferon production in antiviral immunity of macrophages ( 12 ). The present study highlighted that HIPK2 may be a potential target to control excessive cytokine production by overactivated macrophages.…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, another previous study proposed that HIPK2 sustains genomic stability by enhancing DNA damage repair signaling ( 11 ). Apart from the role of HIPK2 that has been elucidated within oncological research, a recent study demonstrated that HIPK2 deficiency leads to the impaired production of type I interferon in macrophages during antiviral immunity ( 12 ). However, the function and mechanism of HIPK2 in anti-microbial immunity remain poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

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HIPK2 sustains inflammatory cytokine production by promoting endoplasmic reticulum stress in macrophages

et al. 2020

Exp Ther Med

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Uncontrolled inflammatory cytokine production by macrophages contributes to numerous conditions, including infection, endotoxemia and sepsis. A previous study proposed that endoplasmic reticulum (ER) stress acts as an essential process in inflammatory cytokine production by macrophages. The present study used a mouse sepsis model and in vitro macrophages to demonstrate that homeodomain-interacting protein kinase 2 (HIPK2) sustained cytokine production in an ER stress-dependent manner. HIPK2 expression was upregulated in the early phase of lipopolysaccharide stimulation. HIPK2 knockdown attenuated IL-6 and TNF-α production, and p65 phosphorylation in macrophages. Furthermore, the attenuated cytokine production was abolished by the ER stress agonist tunicamycin. The activation of ER stress increased the levels of IL-6 and TNF-α, and the phosphorylation of p65, in macrophages following knockdown of HIPK2. Furthermore, HIPK2 inhibition attenuated the production of IL-6 and TNF-α in vitro and in vivo. Therefore, HIPK2 sustained inflammatory cytokine production by promoting ER stress in macrophages. Targeting HIPK2 may be a potential strategy for the management of uncontrolled inflammation in clinical settings.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

HIPK2 sustains inflammatory cytokine production by promoting endoplasmic reticulum stress in macrophages

et al. 2020

Exp Ther Med

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“…Homeodomain-interacting protein kinases (HIPKs; HIPK1-4 in mammals and Hipk in Drosophila [fruit fly]) are protein kinases involved in the regulation of signal transduction (18)(19)(20)(21), cell proliferation and differentiation (22,23), apoptosis (24), stress response (25), embryonic development (26), angiogenesis (27), adipogenesis (28), as well as immune homeostasis (29). The activity of HIPK2 (the most studied member of the mammalian HIPK family) is governed by multiple strategies depending on the environments.…”

mentioning

confidence: 99%

The nutrient sensor OGT regulates Hipk stability and tumorigenic-like activities inDrosophila

Wong

Liu

Parker

et al. 2020

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

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Environmental cues such as nutrients alter cellular behaviors by acting on a wide array of molecular sensors inside cells. Of emerging interest is the link observed between effects of dietary sugars on cancer proliferation. Here, we identify the requirements of hexosamine biosynthetic pathway (HBP) and O-GlcNAc transferase (OGT) for Drosophila homeodomain-interacting protein kinase (Hipk)-induced growth abnormalities in response to a high sugar diet. On a normal diet, OGT is both necessary and sufficient for inducing Hipk-mediated tumor-like growth. We further show that OGT maintains Hipk protein stability by blocking its proteasomal degradation and that Hipk is O-GlcNAcylated by OGT. In mammalian cells, human HIPK2 proteins accumulate posttranscriptionally upon OGT overexpression. Mass spectrometry analyses reveal that HIPK2 is at least O-GlcNAc modified at S852, T1009, and S1147 residues. Mutations of these residues reduce HIPK2 O-GlcNAcylation and stability. Together, our data demonstrate a conserved role of OGT in positively regulating the protein stability of HIPKs (fly Hipk and human HIPK2), which likely permits the nutritional responsiveness of HIPKs.

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“…HIPK1 acted as a novel kinase which was required for optimal B cell function [ 29 ]. HIPK2 deficiency impaired IFN production in macrophages [ 30 ]. HIPK was closely related to immunity.…”

Section: Discussionmentioning

confidence: 99%

Identification of HIPK3 as a potential biomarker and an inhibitor of clear cell renal cell carcinoma

Xiao

Wang

et al. 2021

Aging

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Invasion and metastasis are the main causes of poor prognosis in patients with clear cell renal cell carcinoma (ccRCC). The homeodomain interacting protein kinases (HIPKs) can regulate cell proliferation and apoptosis. Little is known about the prognostic role of HIPKs in ccRCC. Here we use Kaplan-Meier survival analysis and multivariate analysis to analyze the correlation of overall survival (OS) and disease–free survival (DFS). ROC curves analyzed the relationship between clinicopathological parameters and HIPK3 expression in ccRCC. Univariate analysis and multivariate analysis confirmed that the expression of HIPK3 was associated with OS (HR, 0.701; P=0.041) and DFS (HR, 0.630; P=0.012). Low HIPK3 expression was a poor prognostic factor and HIPK3 expression was significantly down-regulated in ccRCC cancer tissues when compared with normal renal tissues. In vitro cell results also confirmed that HIPK3 over-expression could inhibit tumor growth and malignant characteristics. The results indicate that low expression of HIPK3 in ccRCC tissues is significantly associated with poor survival rates in tumor patients, and HIPK3 may be used as a valuable biomarker and inhibitor of ccRCC.

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HIPK2 is necessary for type I interferon–mediated antiviral immunity

Cited by 19 publications

References 58 publications

HIPK2 sustains inflammatory cytokine production by promoting endoplasmic reticulum stress in macrophages

HIPK2 sustains inflammatory cytokine production by promoting endoplasmic reticulum stress in macrophages

The nutrient sensor OGT regulates Hipk stability and tumorigenic-like activities inDrosophila

Identification of HIPK3 as a potential biomarker and an inhibitor of clear cell renal cell carcinoma

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