scholarly journals MKP-1 modulates ubiquitination/phosphorylation of TLR signaling

2021 ◽  
Vol 4 (12) ◽  
pp. e202101137
Author(s):  
Jaya Talreja ◽  
Christian Bauerfeld ◽  
Xiantao Wang ◽  
Markus Hafner ◽  
Yusen Liu ◽  
...  
Keyword(s):  
Tlr Signaling ◽  
Polyubiquitin Chains ◽  
Innate And Adaptive Immunity ◽  
Phosphorylated Form ◽  
Tnf Α ◽  
Specific Protease ◽  
Client Proteins ◽  
Ubiquitin Specific Protease ◽  
Mapk Phosphatase ◽  
First Time

Ubiquitination and phosphorylation are reversible posttranslational protein modifications regulating physiological and pathological processes. MAPK phosphatase (MKP)-1 regulates innate and adaptive immunity. The multifaceted roles of MKP-1 were attributed to dephosphorylation of p38 and JNK MAPKs. We show that the lack of MKP-1 modulates the landscape of ubiquitin ligases and deubiquitinase enzymes (DUBs). MKP-1−/− showed an aberrant regulation of several DUBs and increased expression of proteins and genes involved in IL-1/TLR signaling upstream of MAPK, including IL-1R1, IRAK1, TRAF6, phosphorylated TAK1, and an increased K63 polyubiquitination on TRAF6. Increased K63 polyubiquitination on TRAF6 was associated with an enhanced phosphorylated form of A20. Among abundant DUBs, ubiquitin-specific protease-13 (USP13), which cleaves polyubiquitin-chains on client proteins, was substantially enhanced in murine MKP-1–deficient BMDMs. An inhibitor of USP13 decreased the K63 polyubiquitination on TRAF6, TAK1 phosphorylation, IL-1β, and TNF-α induction in response to LPS in BMDMs. Our data show for the first time that MKP-1 modulates the ligase activity of TRAF6 through modulation of specific DUBs.

scholarly journals MKP-1 modulates Ubiquitination/Phosphorylation of TLR signaling

2021 ◽  
Author(s):  
Jaya Talreja ◽  
Christian Bauerfeld ◽  
Xiantao Wang ◽  
Markus Hafner ◽  
Yusen Liu ◽  
...  
Keyword(s):  
Tlr Signaling ◽  
Polyubiquitin Chains ◽  
Innate And Adaptive Immunity ◽  
Phosphorylated Form ◽  
Tnf Α ◽  
Specific Protease ◽  
Client Proteins ◽  
Ubiquitin Specific Protease ◽  
First Time ◽  
Deficient Mice

Ubiquitination and phosphorylation are reversible post-translational protein modifications regulating physiological and pathological processes. MAPK phosphatase (MKP)-1 regulates innate and adaptive immunity. The multifaceted roles of MKP-1 were attributed to dephosphorylation of p38 and JNK mitogen activated kinases (MAPKs). We show that the lack of MKP-1 modulates the landscape of ubiquitin ligases and deubiquitinase enzymes (DUBs). MKP-1 deficient mice showed an aberrant regulation of several DUBs and increased expression of proteins and genes involved in IL-1/TLR signaling upstream of MAPK, including IL-1R1, IRAK1, TRAF6, phosphorylated TAK1 and an increased K63-polyubiquitination on TRAF6. Increased K63-polyubiquitination on TRAF6 was associated with an enhanced phosphorylated form of A20. Among abundant DUBs, Ubiquitin-specific-protease-13 (USP13), which cleaves polyubiquitin- chains on client proteins, was substantially enhanced in murine MKP-1 deficient BMDMs. An inhibitor of USP13 decreased the K63-polyubiquitination on TRAF6, TAK1-phosphorylation, IL-1β and TNF-α induction in response to LPS in BMDMs. Our data show for the first time that MKP-1 modulates the ligase activity of TRAF6 through modulation of specific DUBs.

Control of AMPK-related kinases by USP9X and atypical Lys29/Lys33-linked polyubiquitin chains

2008 ◽  
Vol 411 (2) ◽  
pp. 249-260 ◽  
Author(s):  
Abdallah K. Al-Hakim ◽  
Anna Zagorska ◽  
Louise Chapman ◽  
Maria Deak ◽  
Mark Peggie ◽  
...  
Keyword(s):  
Topological Analysis ◽  
Deubiquitinating Enzyme ◽  
Wild Type ◽  
Polyubiquitin Chains ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Amp Activated Protein Kinase ◽  
Loop Residue ◽  
In Cells

AMPK (AMP-activated protein kinase)-related kinases regulate cell polarity as well as proliferation and are activated by the LKB1-tumour suppressor kinase. In the present study we demonstrate that the AMPK-related kinases, NUAK1 (AMPK-related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4), are polyubiquitinated in vivo and interact with the deubiquitinating enzyme USP9X (ubiquitin specific protease-9). Knockdown of USP9X increased polyubiquitination of NUAK1 and MARK4, whereas overexpression of USP9X inhibited ubiquitination. USP9X, catalysed the removal of polyubiquitin chains from wild-type NUAK1, but not from a non-USP9X-binding mutant. Topological analysis revealed that ubiquitin monomers attached to NUAK1 and MARK4 are linked by Lys29 and/or Lys33 rather than the more common Lys48/Lys63. We find that AMPK and other AMPK-related kinases are also polyubiquitinated in cells. We identified non-USP9X-binding mutants of NUAK1 and MARK4 and find that these are hyper-ubiquitinated and not phosphorylated at their T-loop residue targeted by LKB1 when expressed in cells, suggesting that polyubiquitination may inhibit these enzymes. The results of the present study demonstrate that NUAK1 and MARK4 are substrates of USP9X and provide the first evidence that AMPK family kinases are regulated by unusual Lys29/Lys33-linked polyubiquitin chains.

scholarly journals Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Ruijie Ye ◽  
Chenhe Su ◽  
Haiyan Xu ◽  
Chunfu Zheng
Keyword(s):  
Innate Immunity ◽  
Signal Pathway ◽  
Innate Immune ◽  
Dna Sensing ◽  
Herpes Simplex Virus 1 ◽  
Polyubiquitin Chains ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The DNA sensing pathway triggers innate immune responses against DNA virus infection, and NF-κB signaling plays a critical role in establishing innate immunity. We report here that the herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP), which is a deubiquitinase (DUB), antagonizes NF-κB activation, depending on its DUB activity. In this study, ectopically expressed UL36USP blocked promoter activation of beta interferon (IFN-β) and NF-κB induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). UL36USP restricted NF-κB activation mediated by overexpression of STING, TANK-binding kinase 1, IκB kinase α (IKKα), and IKKβ, but not p65. UL36USP was also shown to inhibit IFN-stimulatory DNA-induced IFN-β and NF-κB activation under conditions of HSV-1 infection. Furthermore, UL36USP was demonstrated to deubiquitinate IκBα and restrict its degradation and, finally, abrogate NF-κB activation. More importantly, the recombinant HSV-1 lacking UL36USP DUB activity, denoted as C40A mutant HSV-1, failed to cleave polyubiquitin chains on IκBα. For the first time, UL36USP was shown to dampen NF-κB activation in the DNA sensing signal pathway to evade host antiviral innate immunity. IMPORTANCE It has been reported that double-stranded-DNA-mediated NF-κB activation is critical for host antiviral responses. Viruses have established various strategies to evade the innate immune system. The N terminus of the HSV-1 UL36 gene-encoded protein contains the DUB domain and is conserved across all herpesviruses. This study demonstrates that UL36USP abrogates NF-κB activation by cleaving polyubiquitin chains from IκBα and therefore restricts proteasome-dependent degradation of IκBα and that DUB activity is indispensable for this process. This study expands our understanding of the mechanisms utilized by HSV-1 to evade the host antiviral innate immune defense induced by NF-κB signaling.

scholarly journals A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma

Oncogene ◽  
2021 ◽  
Author(s):  
Belamy B. Cheung ◽  
Ane Kleynhans ◽  
Rituparna Mittra ◽  
Patrick Y. Kim ◽  
Jessica K. Holien ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hdac Inhibitor ◽  
Neuroblastoma Cell ◽  
Hdac Inhibitors ◽  
Neuroblastoma Cells ◽  
Transgenic Zebrafish ◽  
Polyubiquitin Chains ◽  
Specific Protease ◽  
Small Molecule Compound ◽  
Ubiquitin Specific Protease

AbstractHistone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.

The ubiquitin-specific protease 8 gene is frequently mutated in adenomas causing Cushing's disease

2015 ◽  
Author(s):  
Luis Gustavo Perez Rivas ◽  
Marily Theodoropoulou ◽  
Francesco Ferrau ◽  
Clara Nusser ◽  
Kohei Kawaguchi ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Cushing's Disease ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

USP48 Sustains Chemoresistance and Metastasis in Ovarian Cancer

2020 ◽  
Vol 20 (9) ◽  
pp. 689-699
Author(s):  
Xuemeng Lei ◽  
Xukun Li ◽  
Hongyan Chen ◽  
Zhihua Liu
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Deubiquitinating Enzymes ◽  
Potential Therapeutic Target ◽  
Kaplan Meier ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Background: Ubiquitin specific protease 48 (USP48) is a member of the deubiquitinating enzymes (DUBs) family. However, the function of USP48 in ovarian cancer remains unclear. Objective: The present study reveals that USP48 knockdown could significantly inhibit cell migration and invasion in ES2, 3AO and A2780 cells, without affecting cell proliferation. Methods: After carboplatin (CBP) treatment, the USP48 ablation increases the apoptosis rate, and the cleaved PARP and cleaved caspase 3 expression levels in ES2, 3AO and A2780 cells. The subcutaneous tumor and intraperitoneally injected experiments demonstrated that the USP48 knockdown significantly increases responsiveness to CBP, and alleviates the metastasis in vivo. Meanwhile, USP48 deficiency results in the improved survival of mice. Results: Finally, the analysis of clinical samples and the TCGA and Kaplan-Meier Plot database revealed that the high expression of USP48 in ovarian cancer patients is associated with poor survival and resistance to CBP therapy. Conclusion: In summary, USP48 may be a potential therapeutic target for ovarian cancer patients.

Sign in / Sign up

Export Citation Format

Share Document