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Mycobacterial metallophosphatase MmpE acts as a nucleomodulin to regulate host gene expression and promote intracellular survival.

Liu Chen | Baojie Duan | Qiang Jiang | Yifan Wang | Yingyu Chen | Lei Zhang | Aizhen Guo
eLife | 2026

Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a major global health challenge. Nucleomodulins, bacterial effectors that target the host cell nuclei, are increasingly recognized as key virulence factors, but their roles in mycobacterial pathogenesis remain incompletely elucidated. Here, we characterize a hypothetical protein Rv2577 (designated MmpE) not only as a Fe³+/Zn²+-dependent metallophosphatase but also as a critical nucleomodulin involved in immune evasion and intracellular persistence. MmpE utilizes two nuclear localization signals, RRR20-22 and RRK460-462, to enter the host cell nucleus, where it binds to the promoter region of the vitamin D receptor (VDR) gene, thereby inhibiting host inflammatory gene expression. Additionally, MmpE regulates the PI3K-Akt-mTOR signaling pathway, thereby arresting lysosome maturation. These actions collectively facilitate immune suppression and promote mycobacterial survival in macrophages and in mice. Our findings identify MmpE as a conserved nucleomodulin in mycobacteria and reveal a novel mechanism of MmpE-mediated intracellular survival.

Pubmed ID: 41848417

Associated grants

  • Agency: Fundamental Research Funds for Central Universities,
    Id: 2662023DKQD001
  • Agency: Talent Start-up Funds of Huazhong Agricultural University,
    Id: 11042310008
  • Agency: National Natural Science Foundation of China,
    Id: 32473123
  • Agency: China Agriculture Research System of MOF and MARA,
    Id: CARS-37
  • Agency: National Key Research and Development Program of China,
    Id: 2021YFD1800403

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This is a list of tools and resources that we have found mentioned in this publication.


Clustal Omega (tool)

RRID:SCR_001591

Software package as multiple sequence alignment tool that uses seeded guide trees and HMM profile-profile techniques to generate alignments between three or more sequences. Accepts nucleic acid or protein sequences in multiple sequence formats NBRF/PIR, EMBL/UniProt, Pearson (FASTA), GDE, ALN/Clustal, GCG/MSF, RSF.

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RefSeq (tool)

RRID:SCR_003496

Collection of curated, non-redundant genomic DNA, transcript RNA, and protein sequences produced by NCBI. Provides a reference for genome annotation, gene identification and characterization, mutation and polymorphism analysis, expression studies, and comparative analyses. Accessed through the Nucleotide and Protein databases.

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HOMER (tool)

RRID:SCR_010881

Software tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.

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National Natural Science Foundation of China (tool)

RRID:SCR_011448

The National Natural Science Foundation of China (NSFC) is an organization directly affiliated to the State Council for the management of the National Natural Science Fund. # In accordance with the guiding principles, policies and plans for the development of science and technology in China and by adopting the operating mechanisms for the National Natural Science Fund which conform to the socialism market economic system, NSFC supports basic research and some of applied research, identifies and fosters talented researchers in the realm of science and technology, accelerates the progress of science and technology, and promotes the socioeconomic development in China by giving full play the guidance and coordinating role of the National Natural Science Fund from the central government. # NSFC is in charge of the management of the National Natural Science Fund. It compiles and promulgates the annual Guide to Programs for basic research and some of applied research, handles applications of research projects, and organizes peer review and select the best projects to support. It endeavors to create an academic environment conducive to innovation. # NSFC cooperates with the Ministry of Science and Technology to formulate the principles, policies and plans for the development of basic research in China. When entrusted, it provides consultation and undertakes related assignments on major issues for the development of high technology and applied research in China. # NSFC gives help and support to other Chinese foundations in natural sciences. # NSFC establishes contacts with governmental departments in charge of science and technology, science foundations and related academic organizations in other countries and carries out international cooperation and exchange. # NSFC is responsible for the administration, supervision and guidance of the subordinated bodies. # NSFC undertakes other tasks entrusted by the State Council and the State Leading Group for Science and Technology and Education.

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featureCounts (tool)

RRID:SCR_012919

A read summarization program, which counts mapped reads for the genomic features such as genes and exons.

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HISAT2 (tool)

RRID:SCR_015530

Graph-based alignment of next generation sequencing reads to a population of genomes.

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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C57BL/6J (tool)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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DYKDDDDK tag Antibody (antibody)

RRID:AB_2918475

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mTOR antibody (antibody)

RRID:AB_2882219

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p70(S6K) antibody (antibody)

RRID:AB_2269787

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Phospho-mTOR (Ser2448) Antibody (antibody)

RRID:AB_2889842

This monoclonal targets Phospho-mTOR (Ser2448)

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AKT antibody (antibody)

RRID:AB_2224574

This polyclonal targets AKT

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Phospho-AKT (Ser473) antibody (antibody)

RRID:AB_2782958

This monoclonal targets Phospho-AKT (Ser473)

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Phospho-p70(S6K) (Thr389) Antibody (antibody)

RRID:AB_3086477

This recombinant targets Phospho-p70(S6K) (Thr389)

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GFP tag antibody (antibody)

RRID:AB_11182611

This monoclonal targets GFP tag

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STRING (data or information resource)

RRID:SCR_005223

Database of known and predicted protein interactions. The interactions include direct (physical) and indirect (functional) associations and are derived from four sources: Genomic Context, High-throughput experiments, (Conserved) Coexpression, and previous knowledge. STRING quantitatively integrates interaction data from these sources for a large number of organisms, and transfers information between these organisms where applicable. The database currently covers 5''214''234 proteins from 1133 organisms. (2013)

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THP-1 (cell line)

RRID:CVCL_0006

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Df(2L)dp-h24/SM6b (organism)

RRID:BDSC_1070

Drosophila melanogaster with name Df(2L)dp-h24/SM6b from BDSC.

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Cytoscape (software resource)

RRID:SCR_003032

Software platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.

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HEK293T (cell line)

RRID:CVCL_0063

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y[2] ct[6] dvr[2] v[1] f[1]/C(1)DX, y[1] f[1] (organism)

RRID:BDSC_1010

Drosophila melanogaster with name y[2] ct[6] dvr[2] v[1] f[1]/C(1)DX, y[1] f[1] from BDSC.

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jVenn (software resource)

RRID:SCR_016343

JavaScript plug-in software application for web environments to analyze data. It is an interactive Venn diagram viewer.Used for comparing lists with Venn Diagrams. It handles up to six input lists and presents results using classical or Edwards-Venn layouts. User interactions can be controlled and customized.

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MEGA Software (software resource)

RRID:SCR_000667

Software integrated tool for conducting automatic and manual sequence alignment, inferring phylogenetic trees, mining web based databases, estimating rates of molecular evolution, and testing evolutionary hypotheses. Used for comparative analysis of DNA and protein sequences to infer molecular evolutionary patterns of genes, genomes, and species over time. MEGA version 4 expands on existing facilities for editing DNA sequence data from autosequencers, mining Web-databases, performing automatic and manual sequence alignment, analyzing sequence alignments to estimate evolutionary distances, inferring phylogenetic trees, and testing evolutionary hypotheses. MEGA version 6 enables inference of timetrees, as it implements RelTime method for estimating divergence times for all branching points in phylogeny.

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UCSF Chimera (data processing software)

RRID:SCR_004097

A highly extensible program for interactive visualization and analysis of molecular structures and related data, including density maps, supramolecular assemblies, sequence alignments, docking results, trajectories, and conformational ensembles. High-quality images and animations can be generated. Chimera includes complete documentation and several tutorials, and can be downloaded free of charge for academic, government, non-profit, and personal use.

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GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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ESPript 2.2 (software resource)

RRID:SCR_006587

A utility, whose output is a PostScript file of aligned sequences with graphical enhancements. Its main input is an ascii file of pre-aligned sequences. Optional files allow further rendering. The program calculates a similarity score for each residue of the aligned sequences. The output shows: * Secondary Structures * Aligned sequences * Similarities * Accessibility * Hydropathy * User-supplied markers * Intermolecular contacts In addition, similarity score can be written in the bfactor column of a pdb file, to enable direct display of highly conserved areas. You can run ESPript from this server with the HTML interface. It is configured for a maximum of 1,000 sequences. Links to webESPript * ENDscript: you can upload a PDB file or enter a PDB code such as 1M85. The programs DSSP and CNS are executed via the interface, so as to obtain an ESPript figure with a lot of structural information (secondary structure elements, intermolecular contacts). You can also find homologous sequences with a BLAST search, perform multiple sequence alignments with MULTALIN or CLUSTALW and create an image with BOBSCRIPT or MOLSCRIPT to show similarities on your 3D structure. * ProDom: you can enter a sequence identifier to find homologous domains, perform multiple sequence alignments with MULTALIN and click on the link to ESPript. * Predict Protein: you can receive a mail in text (do not use the HTML option when you submit your request in Predict Protein) with aligned sequences and numerous information including secondary structure prediction. Click on a special html link to upload your mail in ESPript. * NPS(at): you can execute the programs BLAST and CLUSTALW to obtain multiple alignments. You can predict secondary structure elements and click on the link to ESPript. This program started in the laboratory of Dr Richard Wade at the Institut de Biologie Structurale, Grenoble. It moved later to the Laboratory of Molecular Biophysics in Oxford, then to the Institut de Pharmacologie et de Biologie Structurale in Toulouse. It is now developed in the Laboratoire de BioCristallographie of Dr Richard Haser, Institut de Biologie et de Chimie des Prot��������ines, Lyon and in the Laboratoire de Biologie Mol��������culaire et de Relations Plantes-Organismes, group of Dr Daniel Kahn, Institut National de la Recherche Agronomique de Toulouse.

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RAW264.7/HNP (cell line)

RRID:CVCL_C6XG

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AlphaFold Protein Structure Database (database)

RRID:SCR_023662

Database of protein structure predictions by AlphaFold that are freely and openly available to global scientific community. Included are nearly all catalogued proteins known to science. Provides programmatic access to and interactive visualization of predicted atomic coordinates, per residue and pairwise model confidence estimates and predicted aligned errors.

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iTOL (service resource)

RRID:SCR_018174

Web tool for display, annotation and management of phylogenetic trees. Accessible with any modern web browser.

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SignalP (web application)

RRID:SCR_015644

Web application for prediction of the presence and location of signal peptide cleavage sites in amino acid sequences from different organisms. The method incorporates a prediction of cleavage sites and a signal peptide/non-signal peptide prediction based on a combination of several artificial neural networks.

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CaseViewer (data processing software)

RRID:SCR_017654

Software tool from 3DHISTECH Ltd. designed for work with whole slide images. Digital microscope application for supporting histopathological diagnostic workflow and microscope examination process. Advanced slide viewing software for Windows and Mac used in clinical pathology and research.

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