In vitro ubiquitination of Mycobacterium tuberculosis by E3 ubiquitin ligase, MKRN1

Subrahmanian, Meenu; Jeya, Marimuthu; Sairam, Thiagarajan; Sankaran, Ramalingam

doi:10.1007/s10529-020-02873-6

Cited by 7 publications

(6 citation statements)

References 16 publications

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“…We further explored which host E3 ubiquitin ligases might be involved in the ubiquitination of PPE68. MKRN1, COPS5 and SMURF1 were reported as Mtb -specific host E3 ubiquitin ligases ( 15 , 19 , 30 ). Using Co-IP followed by Western blot, we demonstrated that MKRN1, not COPS5 and SMURF1, interacted with PPE68 ( Figure 2E ), but K166-mutant PPE68 (K166A) almost completely lost binding to MKRN1 compared to WT PPE68 ( Figure 2E ).…”

Section: Resultsmentioning

confidence: 99%

“…Another member, MKRN2, may derive from gene duplication of MKRN1, and is crucial for suppression of the p53/PERP signaling pathway ( 16 , 17 ). Previous studies have demonstrated that MKRN1 was upregulated during Mtb infection and involved in mediating the ubiquitination of Mtb in vitro ( 18 , 19 ), however, its intracellular role during Mtb infection has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Host MKRN1-Mediated Mycobacterial PPE Protein Ubiquitination Suppresses Innate Immune Response

et al. 2022

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Mycobacterium tuberculosis (Mtb), as an important intracellular pathogen, can invade and survive in macrophages and is capable of escaping the clearance of immune system. Despite decades of research efforts, the precise mechanism of immune escape and the virulence factors encoded by Mtb involved remain to be explored. Mtb-specific genomic regions of deletion (RD)-encoded proteins and PE/PPE family proteins have been implicated in immune evasion. Here, we screened more than forty RD-encoded proteins which might be involved in facilitating bacterial survival in macrophages, and found that a Mtb PPE68/Rv3873 protein, encoded by Mtb-RD1, is essential for efficient Mtb intracellular survival in macrophages. In terms of mechanism, we found that the ubiquitin ligase (E3) Makorin Ring Finger Protein 1 (MKRN1) of macrophage interacted with PPE68 and promoted the attachment of lysine (K)-63-linked ubiquitin chains to the K166 site of PPE68. K63-ubiquitination of PPE68 further bound src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) to suppress K63-linked polyubiquitin chains of tumor necrosis factor receptor-associated factor 6 (TRAF6), and then remarkably suppressed TRAF6-driven NF-κB and AP-1 signaling and TNF-α, IL-6 and NO production. We demonstrate that the K63-linked ubiquitination of PPE68 by MKRN1 contributed to the PPE68-mediated mycobacterial immune escape. Our finding identifies a previously unrecognized mechanism by which host MKRN1-mediated-ubiquitination of mycobacterial PPE protein suppresses innate immune responses. Disturbing the interaction between host MKRN1 ubiquitin system and mycobacterial PPE protein might be a potential therapeutic target for tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Host MKRN1-Mediated Mycobacterial PPE Protein Ubiquitination Suppresses Innate Immune Response

et al. 2022

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“…Therefore, we speculated that inhibition and down-regulation of ASB1 in the late stage of infection can against the inflammatory injury induced by Staphylococcus aureus . Makorin ring finger protein 1 (MKRN1) is a ubiquitin ligase, which is vital against viral pathogens [ 41 ]. Some studies displayed that the high expression of MKRN1 can help host cells to defend against infection by inducing ubiquitination of pparγ that is beneficial to M. tuberculosis growth [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Makorin ring finger protein 1 (MKRN1) is a ubiquitin ligase, which is vital against viral pathogens [ 41 ]. Some studies displayed that the high expression of MKRN1 can help host cells to defend against infection by inducing ubiquitination of pparγ that is beneficial to M. tuberculosis growth [ 41 ]. However, there are few studies about the role of MKRN1 in the Staphylococcus aureus .…”

Section: Discussionmentioning

confidence: 99%

Investigation of hub gene associated with the infection of Staphylococcus aureus via weighted gene co-expression network analysis

Huang

et al. 2021

BMC Microbiol

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Introduction Staphylococcus aureus is a gram-positive bacterium that causes serious infection. With the increasing resistance of bacteria to current antibiotics, it is necessary to learn more about the molecular mechanism and cellular pathways involved in the Staphylococcus aureus infection. Methods We downloaded the GSE33341 dataset from the GEO database and applied the weighted gene co-expression network analysis (WGCNA), from which we obtained some critical modules. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were applied to illustrate the biological functions of genes in these modules. We constructed the protein-protein interaction (PPI) network by Cytoscape and selected five candidate hub genes. Five potential hub genes were validated in GSE30119 by GraphPad Prism 8.0. The diagnostic values of these genes were calculated and present in the ROC curve based on the GSE13670 dataset. Their gene functions were analyzed by Gene Set Enrichment Analysis (GSEA). Results A co-expression network was built with 5000 genes divided into 11 modules. The genes in green and turquoise modules demonstrated a high correlation. According to the KEGG and GO analyses, genes in the green module were closely related to ubiquitination and autophagy. Subsequently, we picked out the top five hub genes in the green module. And UBB was determined as the hub gene in the GSE30119 dataset. The expression level of UBB, ASB, and MKRN1 could significantly differentiate between Staphylococcus aureus infection and healthy controls based on the ROC curve. The GSEA analysis indicated that lower expression levels of UBB were associated with the P53 signal pathway. Conclusions We identified some hub genes and significant signal enrichment pathways in Staphylococcus aureus infection via bioinformatics analysis, which may facilitate the development of potential clinical therapeutic strategies.

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“… 81 , 116 – 120 To date, only two E3 ubiquitin ligases, Parkin and Smurf1, have been found to control ubiquitin targeting of Mtb for xenophagy initiation, which was realized through the mediation of K63- and K48-linked ubiquitination of Mtb-associated substrates, respectively. 118 , 119 In addition, a recent study demonstrated that human makorin ring finger protein 1 (MKRN1) is an Mtb-specific E3 ubiquitin ligase that can mediate the ubiquitination of Mtb in vitro in conjunction with ubiquitin-activating enzyme E1 (UBE1) and ubiquitin conjugating enzyme E2 D3 (UBE2D3), 121 although its intracellular role during Mtb infection has not been illustrated. However, the protein substrates on Mtb-containing phagosomes or mycobacterial surfaces that can be ubiquitinated by these E3 ligases remain unidentified.…”

Section: Introductionmentioning

confidence: 99%

New insights into the evasion of host innate immunity by Mycobacterium tuberculosis

et al. 2020

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Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that causes tuberculosis (TB), which remains the leading infectious cause of human death. The early interactions between Mtb and the host innate immune system largely determine the establishment of TB infection and disease development. Upon infection, host cells detect Mtb through a set of innate immune receptors and launch a range of cellular innate immune events. However, these innate defense mechanisms are extensively modulated by Mtb to avoid host immune clearance. In this review, we describe the emerging role of cytosolic nucleic acid-sensing pathways at the host – Mtb interface and summarize recently revealed mechanisms by which Mtb circumvents host cellular innate immune strategies such as membrane trafficking and integrity, cell death and autophagy. In addition, we discuss the newly elucidated strategies by which Mtb manipulates the host molecular regulatory machinery of innate immunity, including the intranuclear regulatory machinery, the ubiquitin system, and cellular intrinsic immune components. A better understanding of innate immune evasion mechanisms adopted by Mtb will provide new insights into TB pathogenesis and contribute to the development of more effective TB vaccines and therapies.

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In vitro ubiquitination of Mycobacterium tuberculosis by E3 ubiquitin ligase, MKRN1

Cited by 7 publications

References 16 publications

Host MKRN1-Mediated Mycobacterial PPE Protein Ubiquitination Suppresses Innate Immune Response

Host MKRN1-Mediated Mycobacterial PPE Protein Ubiquitination Suppresses Innate Immune Response

Investigation of hub gene associated with the infection of Staphylococcus aureus via weighted gene co-expression network analysis

New insights into the evasion of host innate immunity by Mycobacterium tuberculosis

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