OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9

Chen, Xiaorong; Zhang, Honghai; Wang, Xueer; Shao, Zhugui; Li, Yanqi; Zhao, Guimin; Liu, Feng; Liu, Bingyu; Zheng, Yi; Chen, Tian; Zheng, Hui; Zhang, Lei; Gao, Chengjiang

doi:10.4049/jimmunol.2001253

Cited by 20 publications

(17 citation statements)

References 45 publications

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“…For instance, OTUD1 increases Smurf1 expression levels to promote degradation of the MAVS/TRAF3/TRAF6 signalosome and inhibit the innate immune response to viral infection 32 . OTUD1 deubiquitinates CARD9 to modulate antifungal innate immunity 33 . Meanwhile, OTUD1 is lost in multiple types of human cancer 22 and closely associated with cell survival and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

Li¹,

Yan²,

Yu³

et al. 2022

Int. J. Biol. Sci.

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and has the highest mortality rate. For metastatic RCC, systemic drug therapy is the most important method in addition to surgical tumor reduction. In recent years, tyrosine kinase inhibitors (TKIs) targeting the angiogenesis have been applied to treat ccRCC and achieved profound therapeutic effects. It has been reported that most patients receiving antiangiogenic therapy will develop resistance within 15 months. The mechanism of resistance to targeted therapy is extremely complex and has not been clarified. Ovarian tumor-associated protease domain-containing proteins (OTUDs) belonging to DUBs play a critical role in the tumorigenesis of solid tumors. However, the specific role of OTUDs in ccRCC is still elusive. Here, we investigated the clinicopathological role of OTUD family members in ccRCC. We demonstrated that OTUD1 was downregulated in renal cancer and involved in the poor prognosis of renal cancer. Then, we showed that OTUD1 inhibits cancer cell growth. Moreover, analysis of OTUD1 RNA-seq data indicated that OTUD1 inhibition triggers the AKT and NF-kappa B pathways in renal cancer cells. Furthermore, OTUD1 interacts with PTEN and regulates its stability. Subsequently, we revealed that downregulation of OTUD1 contributes to the sensitivity of renal cancer cells to TKIs, and this effect was blocked by TNF/NF-kappa B inhibitors and AKT inhibitors. Thus, we identified that the OTUD1-PTEN axis suppresses tumor growth and regulates the resistance of renal cancer to TKIs.

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Section: Discussionmentioning

confidence: 99%

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

Li¹,

Yan²,

Yu³

et al. 2022

Int. J. Biol. Sci.

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“…OTUD1 deubiquitinates ubiquitinated CARD9, leading to CARD9 activation. Infection of OTUD1 homozygous knockout mice with C. albicans led to reduced mouse survival and increased fungal burden in kidney, lung and spleen slices compared to wild type mice [ 135 ]. OTUD1 mutations may cause susceptibility to C. albicans infection through CARD9 deficiency ( Figure 2 ), highlighting a novel cause of CMC and introducing a potential therapeutic target for treatment of CARD9 deficiency.…”

Section: Failures Of Innate Immunity In Diseasementioning

confidence: 99%

“…STAT1 gain of function mutations increase sensitivity to IFNs, leading to increased susceptibility to fungal infections [ 131 ]. OTUD1 or MyD88 deficiencies result in reduced transcription of NF-κB, resulting in reduced inflammatory response and increased C. albicans burden [ 135 , 138 ]. CARD9 deficiency causes reduced NF-κB transcription, resulting in reduced inflammatory response and increased A. fumigatus burden [ 147 ].…”

Section: Failures Of Innate Immunity In Diseasementioning

confidence: 99%

A Fun-Guide to Innate Immune Responses to Fungal Infections

Burgess

Condliffe²,

Elks³

2022

JoF

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Immunocompromised individuals are at high risk of developing severe fungal infections with high mortality rates, while fungal pathogens pose little risk to most healthy people. Poor therapeutic outcomes and growing antifungal resistance pose further challenges for treatments. Identifying specific immunomodulatory mechanisms exploited by fungal pathogens is critical for our understanding of fungal diseases and development of new therapies. A gap currently exists between the large body of literature concerning the innate immune response to fungal infections and the potential manipulation of host immune responses to aid clearance of infection. This review considers the innate immune mechanisms the host deploys to prevent fungal infection and how these mechanisms fail in immunocompromised hosts. Three clinically relevant fungal pathogens (Candida albicans, Cryptococcus spp. and Aspergillus spp.) will be explored. This review will also examine potential mechanisms of targeting the host therapeutically to improve outcomes of fungal infection.

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“…As demonstrated for transaldolase, cysteines can covalently bind lysines via a sulfur-oxygen-nitrogen bridge that acts as an allosteric redox switch. 10 As new insights emerge from this continuing debate, new opportunities to identify novel targets in VWF to promote hemostasis in bleeding disorders or to abrogate platelet adhesion in thrombotic disorders will arise.…”

mentioning

confidence: 99%

Targeting a deubiquitinase blocks GVHD

Frattini¹

2023

Blood

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the different fates of the functional groups (eg, thiol, sulfenic acid, or their derivatives) and their ramifications would also be important to consider. As demonstrated for transaldolase, cysteines can covalently bind lysines via a sulfur-oxygen-nitrogen bridge that acts as an allosteric redox switch. 10 As new insights emerge from this continuing debate, new opportunities to identify novel targets in VWF to promote hemostasis in bleeding disorders or to abrogate platelet adhesion in thrombotic disorders will arise.

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OTUD1 Regulates Antifungal Innate Immunity through Deubiquitination of CARD9

Cited by 20 publications

References 45 publications

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

A Fun-Guide to Innate Immune Responses to Fungal Infections

Targeting a deubiquitinase blocks GVHD

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