Junli Sheng

State Key Laboratory of Respiratory Disease

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Shengfeng Hu

Southern Medical University

Yitian Chen

Southern Medical University

Shitong He

Southern Medical University

Yuling Fu

Southern Medical University

Xiaolong You

Southern Medical University

Dingnai Nie

State Key Laboratory of Respiratory Disease

Yulan Huang

Southern University of Science and Technology

Xiaoxia Zhan

Sun Yat-sen University

Zhijie Zeng

Fujian Electric Power Survey & Design Institute

Haiyan Mai

Southern Medical University

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Southern Medical University

Sun Yat-sen University

Guangzhou Medical University

State Key Laboratory of Respiratory Disease

Second Affiliated Hospital of Guangzhou Medical University

The First Affiliated Hospital, Sun Yat-sen University

Zhujiang Hospital

Nanfang Hospital

Nanjing Medical University

Huazhong University of Science and Technology

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USP12 positively regulates M‐MDSC function to inhibit antitumour immunity through deubiquitinating and stabilizing p65

Immunology (2022)

Xiaoxia Zhan Qiuying He Junli Sheng Xiaobing Jiang Letao Lin

Abstract The relative abundance of myeloid‐derived suppressor cells (MDSCs) compared to cytotoxic T cells determines the outcomes of diseases and the efficacy of immunotherapy. Ubiquitin‐specific peptidase 12 (USP12), a member of the USP family of deubiquitinases, targets multiple signalling pathways and regulates diverse biological processes, including cell proliferation and survival. It is well known that ubiquitylation is an important mechanism for regulating the immune response. However, it is unclear whether USP12 regulates tumour growth by influencing MDSCs. In the present study, we reported that USP12 deficiency decreased infiltration and impaired the suppressor function of monocytic (M)‐MDSCs, resulting in increased CD8 + T‐cell response and decelerated tumour growth. USP12‐knockout M‐MDSCs were less potent in inhibiting the proliferation of CD8 + T cells and their ability to secrete IFN‐γ. Furthermore, USP12 deficiency inhibited the suppressor function of M‐MDSCs by downregulating the negative regulatory molecules inducible nitric oxide synthase and PD‐L1, through deubiquitinating and stabilizing p65. Our results suggest that USP12 is a positive regulator of M‐MDSCs and may serve as a potential target for antitumor therapy.

Deubiquitinating enzyme

Myeloid-derived Suppressor Cell

10.1111/imm.13552

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Citations (13)

The E3 Ubiquitin Ligase HERC5 Promotes Antimycobacterial Immunity in Macrophages Through Regulating ISGylation and Degradation of PTEN

SSRN Electronic Journal (2021)

Xialin Du Junli Sheng Shitong He Yalong Yang Yulan Huang

HERC5 (homologous to mouse HERC6) is an E3 enzyme that mediates interferon-stimulated gene 15 (ISG15)-induced ISGylation of protein targets to inhibit protein function, thereby playing a vital role in various physiological functions. However, the direct role of HERC5 in macrophages after M. tuberculosis infection has not yet been studied. In the present study, we showed that HERC5 plays a vital role in promoting the inflammatory immune response. HERC5 deficiency in macrophages enhanced bacterial growth, both in vitro and in vivo. We demonstrated that HERC5 increased pro-inflammatory cytokine production in macrophages by positively regulating the PI3K-AKT signaling pathway. Finally, we found that HERC5 regulated PTEN ISGylation and degradation, thereby promoting activation of the PI3K-AKT signaling pathway. Our findings identified an essential role of HERC5 in the ISGylation of PTEN and contributed to our understanding of its protective effects against M. tuberculosis infection. Therefore, HERC5 is a potential target for therapeutic intervention against tuberculosis.Funding Information: This work was supported National Natural Science Foundation of China (81772150, 81901614, 82072242, 82070906), Guangdong Basic and Applied Basic Research Foundation (2019A1515011103).Declaration of Interests: The authors declare no competing financial interests.Ethics Approval Statement: All the mice were maintained under specific pathogen-free conditions with the approval of the Scientific Investigation Board of the Biosafety Management Committee of Southern Medical University

Antimycobacterial

Degradation

10.2139/ssrn.3912537

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USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ

Cellular and Molecular Immunology (2023)

Xiaotong Zhu Peng Wang Xiaoxia Zhan Yuping Zhang Junli Sheng

Deubiquitinating enzyme

10.1038/s41423-022-00969-9

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Citations (20)

TRIM11 attenuates Treg cell differentiation by p62-selective autophagic degradation of AIM2

Cell Reports (2023)

Ting Yu Xiaofan Yang Qiang Fu Liang Junyu Xinger Wu

Ubiquitination is an important protein modification that regulates diverse biological processes, including CD4+ T cell differentiation and functions. However, the function of most E3 ubiquitin ligases in CD4+ T cell differentiation and CD4+ T cell-mediated pathological diseases remains unclear. In this study, we find that tripartite motif-containing motif 11 (TRIM11) specifically negatively regulates regulatory T (Treg) cell differentiation in CD4+ T cells and promotes autoimmune disease development in an AIM2-dependent manner. Mechanistically, TRIM11 interacts with absent in melanoma 2 (AIM2) and promotes the selective autophagic degradation of AIM2 by inducing AIM2 ubiquitination and binding to p62 in CD4+ T cells. AIM2 attenuates AKT and FOXO1 phosphorylation, MYC signaling, and glycolysis, thereby promoting the stability of Treg cells during experimental autoimmune encephalomyelitis (EAE). Our findings suggest that TRIM11 serves as a potential target for immunotherapeutic intervention for dysregulated immune responses that lead to autoimmunity and cancers.

AIM2

10.1016/j.celrep.2023.113231

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USP12 promotes antiviral responses by deubiquitinating and stabilizing IFI16

PLoS Pathogens (2023)

Yuling Fu Xiaoxia Zhan Xiaolong You Dingnai Nie Haiyan Mai

Deubiquitinating enzymes (DUBs) regulate antiviral immune response through targeting DNA sensor signaling pathway members. As one of the DNA sensors, interferon (IFN)-γ inducible protein 16 (IFI16) play a major role in response to virus infections through activating the canonical STING/TBK-1/IRF3 signaling pathway. Only a few studies discuss the function of DUBs in IFI16-mediated antiviral response. Ubiquitin-specific protease 12 (USP12), which is one of the major members of the USP family, participates in various biological functions. However, whether USP12 regulates the nucleic acid sensor to modulate antiviral immune responses has not yet been elucidated. In this study, we found that knockout or knockdown of USP12 impaired the HSV-1-induced expressions of IFN-β, CCL-5, IL-6, and downstream interferon-stimulated genes (ISGs). Moreover, USP12 deficiency increased HSV-1 replication and host susceptibility to HSV-1 infection. Mechanistically, USP12 inhibited the proteasome-dependent degradation of IFI16 through its deubiquitinase activity, thereby maintaining IFI16 stability and promoting IFI16-STING-IRF3- and p65-mediated antiviral signaling. Overall, our findings demonstrate an essential role of USP12 in DNA-sensing signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.

Deubiquitinating enzyme

IRF3

10.1371/journal.ppat.1011480

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Citations (9)

UCHL1 Promoted Polarization of M1 Macrophages by Regulating the PI3K/AKT Signaling Pathway

Journal of Inflammation Research (2022)

Yulan Huang Shitong He Yitian Chen Junli Sheng Yuling Fu

As deubiquitinases (DUBs), ubiquitin C-terminal hydrolase (UCH)-L1 has been shown to play a crucial role in regulating diverse biological processes. However, its function in macrophage polarization remains unclear.We performed in vivo and in vitro experiments to investigate the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a kind of DUBs, in macrophage differentiation by using UCHL1-deficiency mice.We demonstrated that LPS stimulation induced UCHL1 expression in macrophages. The deficiency of UCHL1 expression decreased the expression of CD80 and CD86 but increased the expression of CD206. The expression of TNF-α, IL-6, iNOS, and IL-10 was downregulated, while that of Arg1, Ym1, and Fizz1 was upregulated in UCHL1 deficient macrophages. Moreover, we observed that UCHL1 promoted the degradation of p110α through autophagy, but paradoxically increased the activity of AKT, thereby promoting polarization of macrophages into pro-inflammatory states.In this study, we identified UCHL1 as a positive regulator of M1 macrophage polarization. Our findings may help in developing therapeutic interventions for the treatment of inflammatory diseases and pathogenic infections.

Macrophage polarization

CD86

CD80

10.2147/jir.s343487

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Citations (13)

Pam2 lipopeptides enhance the immunosuppressive activity of monocytic myeloid-derived suppressor cells by STAT3 signal in chronic inflammation

Central European Journal of Immunology (2022)

Xiaoxia Zhan Xiaobing Jiang Qiuying He Liangyin Zhong Yichong Wang

Chronic inflammation develops when the immune system is unable to clear a persistent insult. Unresolved chronic inflammation leads to immunosuppression to maintain the internal homeostatic conditions, which is mediated primarily by myeloid-derived suppressor cells (MDSCs). Toll-like receptors 2 (TLR2) has an important role in chronic inflammation and can be activated by a vast number and diversity of TLR2 ligands, for example Pam2CSK4. However, the regulatory effect of TLR2 signaling on MDSCs in chronic inflammation remains controversial. This study demonstrated that heat-killed Mycobacterium bovis BCG-induced pathology-free chronic inflammation triggered suppressive monocytic MDSCs (M-MDSCs) that expressed TLR2. Activation of TLR2 signaling by Pam2CSK4 treatment enhanced immunosuppression of M-MDSCs by upregulating inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production partly through signal transducer and activator of transcription 3 (STAT3) activation. Thus, TLR2 has a fundamental role in promoting the MDSC-mediated immunosuppressive environment during chronic inflammation and might represent a potentially therapeutic target in chronic inflammation disease.

Myeloid-derived Suppressor Cell

Immunosuppression

10.5114/ceji.2022.113086

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Citations (1)

RNF157 attenuates CD4⁺ T cell-mediated autoimmune response by promoting HDAC1 ubiquitination and degradation

Theranostics (2023)

Peng Wang Jingjing Zhao Yunke Tan Junli Sheng Shitong He

Background: CD4 + T cells play an important role in body development and homeostasis.Quantitative and functional changes in CD4 + T cells result in abnormal immune responses, which lead to inflammation, cancer, or autoimmune diseases, such as multiple sclerosis (MS).Ubiquitination plays an essential role in the differentiation and functioning of CD4 + T cells.However, the function of several E3 ubiquitin ligases in CD4 + T cell differentiation and T cell-mediated pathological diseases remains unclear.Methods: RNA sequencing data were analyzed to identify the E3 ubiquitin ligases that participate in the pathogenesis of MS.Furthermore, conditional knockout mice were generated.Specifically, flow cytometry, qPCR, western blot, CO-IP and cell transfer adoptive experiments were performed.Results: In this study, we identified The RING finger 157 (RNF157) as a vital regulator of CD4 + T cell differentiation; it promoted Th1 differentiation but attenuated Th17 differentiation and CCR4 and CXCR3 expressions in CD4 + T cells, thereby limiting experimental autoimmune encephalomyelitis development.Mechanistically, RNF157 in CD4 + T cells targeted HDAC1 for K48-linked ubiquitination and degradation.Notably, RNF157 expression was significantly decreased and showed a significant negative correlation with RORγt expression in patients with MS. Conclusions:Our study highlights the critical role of RNF157 in regulating CD4 + T cell functions in autoimmune diseases and suggests RNF157 as a potential target in adaptive immune responses against MS and other autoimmune disorders.

10.7150/thno.86307

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The E3 ligase HERC5 promotes antimycobacterial responses in macrophages by ISGylating the phosphatase PTEN

Science Signaling (2023)

Xialin Du Junli Sheng Yitian Chen Shitong He Yalong Yang

Innate immune signaling in macrophages during viral infection is regulated by ISGylation, the covalent attachment of the ubiquitin-like protein interferon-stimulated gene 15 (ISG15) to protein targets. Here, we explored the role of ISGylation in the macrophage response to infection with Mycobacterium tuberculosis . In human and mouse macrophages, the E3 ubiquitin ligases HERC5 and mHERC6, respectively, mediated the ISGylation of the phosphatase PTEN, which promoted its degradation. The decreased abundance of PTEN led to an increase in the activity of the PI3K-AKT signaling pathway, which stimulated the synthesis of proinflammatory cytokines. Bacterial growth was increased in culture and in vivo when human or mouse macrophages were deficient in the major E3 ISG15 ligase. The findings expand the role of ISGylation in macrophages to antibacterial immunity and suggest that HERC5 signaling may be a candidate target for adjunct host-directed therapy in patients with tuberculosis.

Antimycobacterial

Tensin

10.1126/scisignal.abm1756

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Citations (3)

Correction: USP12 promotes antiviral responses by deubiquitinating and stabilizing IFI16

PLoS Pathogens (2023)

Yuling Fu Xiaoxia Zhan Xiaolong You Dingnai Nie Haiyan Mai

After this article [1] was published, questions were raised about errors in the gene nomenclature used and missing details in the Methods.In response to queries about the mouse models, the corresponding author stated that p204/ Ifi204 is the mouse ortholog of human IFI16, and that the gene IFI16 was referred to in error, instead of the gene p204.The corresponding author therefore provided the below updated versions of Figs 5-7, S8 Fig, and S10 Fig, where IFI16 has been replaced with p204 in the captions and axes labels.There are also areas throughout the text where IFI16 should be replaced with p204.The corresponding author stated that the antibody used to detect p204 is NBP2-27153 from Novus and has provided an updated S1 Text file (S3 File) with qPCR primers and Accession ID for p204 (IFI204) here.The corresponding author provided some clarifying information on the origin of the mouse source: the USP12-deficient (Usp12-/-) mice were generated by Cyagen Biosciences Inc. [2].P204-/-(or Ifi204-/-) mice were built by Shanghai Research Center for Model Organisms [3].The corresponding author also provided western blots to support that the ifi204 -/mice are lacking ifi204 and the double KO mice are missing USP12 and ifi204 in S4 File.

Deubiquitinating enzyme

10.1371/journal.ppat.1011827

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