scholarly journals Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila

2018 ◽  
Author(s):  
Alexandre Cammarata-Mouchtouris ◽  
Xuan-Hung Nguyen ◽  
François Bonnay ◽  
Akira Goto ◽  
Amir Orian ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
E3 Ubiquitin Ligase ◽  
Microbial Infection ◽  
Immune Effector ◽  
Imd Pathway ◽  
Immune Challenges ◽  
Subsequent Activation

One Sentence SummaryUpon microbial infection in Drosophila, the E3-ubiquitin ligase Hyd ubiquitinylates the NF-κB co-factor Akirin for its efficient binding to the NF-κB factor Relish and subsequent activation of immune effectors genes.ABSTRACTThe Drosophila IMD pathway is activated upon microbial challenge with Gramnegative bacteria to trigger the innate immune response. In order to decipher this NF-κB signaling pathway, we undertook an ex-vivo RNAi screen targeting specifically E3 ubiquitin ligases and identified the HECT E3 ubiquitin ligase Hyperplastic Discs “Hyd” as a new actor of the IMD pathway. We showed that Hyd targets the NF-κB cofactor of Akirin. The K63-polyubiquitination chains deposited by Hyd decorate Akirin for its efficient binding to the NF-κB transcription factor Relish. We showed that this Hyd-mediated interaction is critical to activate immune-induced genes that depend on both Relish and Akirin, but is dispensable for those that depend solely on Relish. Therefore Hyd is key in operating a NF-κB transcriptional selectivity downstream of the IMD pathway. Drosophila depleted for Hyd or Akirin failed to express the full set of immune-induced anti-microbial peptide coding genes and succumbed to immune challenges. We showed further that Ubr5, the mammalian homolog of Hyd, is also required downstream of the NF-κB pathway for the IL1β-mediated IL6 activation. This study links the action of a E3-ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.

E3 ubiquitin ligase tripartite motif 7 positively regulates the TLR4-mediated immune response via its E3 ligase domain in macrophages

2019 ◽  
Vol 109 ◽  
pp. 126-133 ◽  
Author(s):  
Mingfeng Lu ◽  
Xuhui Zhu ◽  
Zhizhou Yang ◽  
Wei Zhang ◽  
Zhaorui Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
E3 Ligase ◽  
Tripartite Motif

scholarly journals PRMT5 epigenetically regulates the E3 ubiquitin ligase ITCH to influence lipid accumulation during mycobacterial infection

2021 ◽  
Author(s):  
Salik Miskat Borbora ◽  
R.S. Rajmani ◽  
Kithiganahalli N Balaji
Keyword(s):  
Ubiquitin Ligase ◽  
Lipid Accumulation ◽  
Ex Vivo ◽  
E3 Ubiquitin Ligase ◽  
Mycobacterial Infection ◽  
Drug Regimen ◽  
Loss Of Function ◽  
Methyl Transferase ◽  
Accumulation Of Lipids

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), triggers enhanced accumulation of lipids to generate foamy macrophages (FMs). This process has been often attributed to the surge in the expression of lipid influx genes with a concomitant decrease in those involved in lipid efflux genes. Here, we define an Mtb-orchestrated modulation of the ubiquitination mechanism of lipid accumulation markers to enhance lipid accretion during infection. We find that Mtb infection represses the expression of the E3 ubiquitin ligase, ITCH, resulting in the sustenance of key lipid accrual molecules viz. ADRP and CD36, that are otherwise targeted by ITCH for proteasomal degradation. In line, overexpressing ITCH in Mtb-infected cells was found to suppress Mtb-induced lipid accumulation. Molecular analyses including loss-of-function and ChIP assays demonstrated a role for the concerted action of the transcription factor YY1 and the arginine methyl transferase PRMT5 in restricting the expression of Itch gene by conferring repressive symmetrical H4R3me2 marks on its promoter. Consequently, siRNA-mediated depletion of YY1 or PRMT5 rescued ITCH expression, thereby compromising the levels of Mtb-induced ADRP and CD36 and limiting FM formation during infection. Accumulation of lipids within the host has been implicated as a pro-mycobacterial process that aids in pathogen persistence and dormancy. In our study, perturbation of PRMT5 enzyme activity resulted in compromised lipid levels and reduced mycobacterial survival in primary murine macrophages (ex vivo) and in a therapeutic mouse model of TB infection (in vivo). These findings provide new insights on the role of PRMT5 and YY1 in augmenting mycobacterial pathogenesis. Thus, we posit that our observations could help design novel adjunct therapies and combinatorial drug regimen for effective anti-TB strategies.

scholarly journals TaClpS1, Negatively Regulates Wheat Resistance Against Puccinia striiformis f. sp. tritici

2020 ◽  
Author(s):  
Qian Yang ◽  
Md Ashraful Islam ◽  
Kunyan Cai ◽  
Shuxin Tian ◽  
Yan Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
Puccinia Striiformis ◽  
E3 Ubiquitin Ligase ◽  
Transit Peptide ◽  
26S Proteasome ◽  
Plant Responses ◽  
Virus Induced Gene Silencing ◽  
Chloroplast Transit Peptide

Abstract Background: The degradation of intracellular proteins plays an essential role in plant responses to stressful environments. ClpS1 and E3 ubiquitin ligase function as adaptors for selecting target substrates in caseinolytic peptidase (Clp) proteases pathways and the 26S proteasome system, respectively. Currently, the role of E3 ubiquitin ligase in the plant immune response to pathogens is well defined. However, the role of ClpS1 in the plant immune response to pathogens remains unknown. Results: Here, we identified and characterized wheat (Triticum aestivum) ClpS1 (TaClpS1). TaClpS1 encoded 161 amino acids, contained a conserved ClpS domain and a chloroplast transit peptide (1-32 aa). TaClpS1 was found to be specifically localized in the chloroplast when expressed transiently in wheat protoplasts. The transcript level of TaClpS1 in wheat was significantly induced during infection by Puccinia striiformis f. sp. tritici (Pst). Knock-down of TaClpS1 via virus-induced gene silencing (VIGS) resulted in an increase in resistance against Pst, accompanied by an increase in the hypersensitive response (HR), accumulation of reactive oxygen species (ROS) and expression of TaPR1 and TaPR2, and a reduction in the growth of Pst. Furthermore, heterologous expression of TaClpS1 in Nicotiana benthamiana enhanced the infection by Phytophthora parasitica. Conclusions: These results suggest that TaClpS1 negatively regulates the resistance of wheat to Pst.

scholarly journals TaClpS1, Negatively Regulates Wheat Resistance Against Puccinia striiformis f. sp. tritici

2020 ◽  
Author(s):  
Qian Yang ◽  
Md Ashraful Islam ◽  
Kunyan Cai ◽  
Shuxin Tian ◽  
Yan Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
Puccinia Striiformis ◽  
E3 Ubiquitin Ligase ◽  
Transit Peptide ◽  
26S Proteasome ◽  
Plant Responses ◽  
Virus Induced Gene Silencing ◽  
Chloroplast Transit Peptide

Abstract Background: The degradation of intracellular proteins plays an essential role in plant responses to stressful environments. ClpS1 and E3 ubiquitin ligase function as adaptors for selecting target substrates in caseinolytic peptidase (Clp) proteases pathways and the 26S proteasome system, respectively. Currently, the role of E3 ubiquitin ligase in the plant immune response to pathogens is well defined. However, the role of ClpS1 in the plant immune response to pathogens remains unknown. Results: Here, wheat (Triticum aestivum) ClpS1 (TaClpS1) was studied and resulted to encode 161 amino acids, containing a conserved ClpS domain and a chloroplast transit peptide (1-32 aa). TaClpS1 was found to be specifically localized in the chloroplast when expressed transiently in wheat protoplasts. The transcript level of TaClpS1 in wheat was significantly induced during infection by Puccinia striiformis f. sp. tritici (Pst). Knockdown of TaClpS1 via virus-induced gene silencing (VIGS) resulted in an increase in wheat resistance against Pst, accompanied by an increase in the hypersensitive response (HR), accumulation of reactive oxygen species (ROS) and expression of TaPR1 and TaPR2, and a reduction in the number of haustoria, length of infection hypha and infection area of Pst. Furthermore, heterologous expression of TaClpS1 in Nicotiana benthamiana enhanced the infection by Phytophthora parasitica. Conclusions: These results suggest that TaClpS1 negatively regulates the resistance of wheat to Pst.

scholarly journals TaClpS1, Negatively Regulates Wheat Resistance Against Puccinia striiformis f. sp. tritici

2020 ◽  
Author(s):  
Qian Yang ◽  
Md Ashraful Islam ◽  
Kunyan Cai ◽  
Shuxin Tian ◽  
Yan Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
Puccinia Striiformis ◽  
E3 Ubiquitin Ligase ◽  
Transit Peptide ◽  
26S Proteasome ◽  
Plant Responses ◽  
Virus Induced Gene Silencing ◽  
Chloroplast Transit Peptide

Abstract Background: The degradation of intracellular proteins plays an essential role in plant responses to stressful environments. ClpS1 and E3 ubiquitin ligase function as adaptors for selecting target substrates in caseinolytic peptidase (Clp) proteases pathways and the 26S proteasome system, respectively. Currently, the role of E3 ubiquitin ligase in the plant immune response to pathogens is well defined. However, the role of ClpS1 in the plant immune response to pathogens remains unknown. Results: Here, wheat (Triticum aestivum) ClpS1 (TaClpS1) was studied and resulted to encode 161 amino acids, containing a conserved ClpS domain and a chloroplast transit peptide (1-32 aa). TaClpS1 was found to be specifically localized in the chloroplast when expressed transiently in wheat protoplasts. The transcript level of TaClpS1 in wheat was significantly induced during infection by Puccinia striiformis f. sp. tritici (Pst). Knockdown of TaClpS1 via virus-induced gene silencing (VIGS) resulted in an increase in wheat resistance against Pst, accompanied by an increase in the hypersensitive response (HR), accumulation of reactive oxygen species (ROS) and expression of TaPR1 and TaPR2, and a reduction in the number of haustoria, length of infection hypha and infection area of Pst. Furthermore, heterologous expression of TaClpS1 in Nicotiana benthamiana enhanced the infection by Phytophthora parasitica. Conclusions: These results suggest that TaClpS1 negatively regulates the resistance of wheat to Pst.

scholarly journals E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

2021 ◽  
Author(s):  
Yuhua Shi ◽  
Yang Yang ◽  
Weilv Xu ◽  
Wei Xu ◽  
Xinyu Fu ◽  
...  
Keyword(s):  
Cell Death ◽  
Ubiquitin Ligase ◽  
Essential Role ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
E3 Ubiquitin Ligase ◽  
Positive Regulator ◽  
Ldh Release

Gasdermin D (GSDMD) participates in activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.

scholarly journals TaClpS1, Negatively Regulates Wheat Resistance Against Puccinia striiformis f. sp. tritici

2020 ◽  
Author(s):  
Qian Yang ◽  
Md Ashraful Islam ◽  
Kunyan Cai ◽  
Shuxin Tian ◽  
Yan Liu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
Puccinia Striiformis ◽  
E3 Ubiquitin Ligase ◽  
Transit Peptide ◽  
26S Proteasome ◽  
Plant Responses ◽  
Virus Induced Gene Silencing ◽  
Chloroplast Transit Peptide

Abstract Background: The degradation of intracellular proteins plays an essential role in plant responses to stressful environments. ClpS1 and E3 ubiquitin ligase function as adaptors for selecting target substrates in caseinolytic peptidase (Clp) proteases pathways and the 26S proteasome system, respectively. Currently, the role of E3 ubiquitin ligase in the plant immune response to pathogens is well defined. However, the role of ClpS1 in the plant immune response to pathogens remains unknown. Results: Here, wheat (Triticum aestivum) ClpS1 (TaClpS1) was studied and resulted to encode 161 amino acids, containing a conserved ClpS domain and a chloroplast transit peptide (1-32 aa). TaClpS1 was found to be specifically localized in the chloroplast when expressed transiently in wheat protoplasts. The transcript level of TaClpS1 in wheat was significantly induced during infection by Puccinia striiformis f. sp. tritici (Pst). Knockdown of TaClpS1 via virus-induced gene silencing (VIGS) resulted in an increase in wheat resistance against Pst, accompanied by an increase in the hypersensitive response (HR), accumulation of reactive oxygen species (ROS) and expression of TaPR1 and TaPR2, and a reduction in the number of haustoria, length of infection hypha and infection area of Pst. Furthermore, heterologous expression of TaClpS1 in Nicotiana benthamiana enhanced the infection by Phytophthora parasitica. Conclusions: These results suggest that TaClpS1 negatively regulates the resistance of wheat to Pst.

scholarly journals The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response

2017 ◽  
Vol 13 (3) ◽  
pp. e1006264 ◽  
Author(s):  
Qiang Wang ◽  
Liyuan Huang ◽  
Ze Hong ◽  
Zhongshi Lv ◽  
Zhaomin Mao ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Innate Immune

scholarly journals p47 licenses activation of the immune deficiency pathway in the tick Ixodes scapularis

2018 ◽  
Vol 116 (1) ◽  
pp. 205-210 ◽  
Author(s):  
Erin E. McClure Carroll ◽  
Xiaowei Wang ◽  
Dana K. Shaw ◽  
Anya J. O’Neal ◽  
Adela S. Oliva Chávez ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Ubiquitin Ligase ◽  
Ixodes Scapularis ◽  
Microbial Colonization ◽  
Signaling Cascades ◽  
Regulatory Subunit ◽  
Dependent Manner ◽  
Microbial Infection ◽  
Imd Pathway ◽  
Molecular Rheostat

The E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) acts as a molecular rheostat for the immune deficiency (IMD) pathway of the tick Ixodes scapularis. How XIAP activates the IMD pathway in response to microbial infection remains ill defined. Here, we identified the XIAP enzymatic substrate p47 as a positive regulator of the I. scapularis IMD network. XIAP polyubiquitylates p47 in a lysine 63-dependent manner and interacts with the p47 ubiquitin-like (UBX) module. p47 also binds to Kenny (IKKγ/NEMO), the regulatory subunit of the inhibitor of nuclear factor (NF)- κB kinase complex. Replacement of the amino acid lysine to arginine within the p47 linker region completely abrogated molecular interactions with Kenny. Furthermore, mitigation of p47 transcription levels through RNA interference in I. scapularis limited Kenny accumulation, reduced phosphorylation of IKKβ (IRD5), and impaired cleavage of the NF-κB molecule Relish. Accordingly, disruption of p47 expression increased microbial colonization by the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agent Anaplasma phagocytophilum. Collectively, we highlight the importance of ticks for the elucidation of paradigms in arthropod immunology. Manipulating immune signaling cascades within I. scapularis may lead to innovative approaches to reducing the burden of tick-borne diseases.

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