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Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth

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Listed:
  • Nelson V. Simwela

    (Cornell University)

  • Luana Johnston

    (Cornell University)

  • Paulina Pavinski Bitar

    (Cornell University)

  • Eleni Jaecklein

    (UMass Chan Medical School)

  • Craig Altier

    (Cornell University)

  • Christopher M. Sassetti

    (UMass Chan Medical School)

  • David G. Russell

    (Cornell University)

Abstract

The eukaryotic Glucose Induced Degradation/C-Terminal to LisH (GID/CTLH) complex is a highly conserved E3 ubiquitin ligase involved in a broad range of biological processes. However, a role of this complex in host anti-microbial defenses has not been described. We exploited Mycobacterium tuberculosis (Mtb) induced cytotoxicity in macrophages in a FACS based CRISPR genetic screen to identify host determinants of intracellular Mtb growth restriction. Our screen identified 5 (GID8, YPEL5, WDR26, UBE2H, MAEA) of the 12 predicted members of the GID/CTLH complex as determinants of intracellular growth of both Mtb and Salmonella serovar Typhimurium. We show that the anti-microbial properties of the GID/CTLH complex knockout macrophages are mediated by enhanced GABAergic signaling, activated AMPK, increased autophagic flux and resistance to Mtb induced necrotic cell death. Meanwhile, Mtb isolated from GID/CTLH knockout macrophages are nutritionally starved and oxidatively stressed. Our study identifies the GID/CTLH complex activity as broadly suppressive of host anti-microbial responses against intracellular bacterial infections.

Suggested Citation

  • Nelson V. Simwela & Luana Johnston & Paulina Pavinski Bitar & Eleni Jaecklein & Craig Altier & Christopher M. Sassetti & David G. Russell, 2024. "Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53637-z
    DOI: 10.1038/s41467-024-53637-z
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    References listed on IDEAS

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    1. Bassam K. Kudhair & Andrea M. Hounslow & Matthew D. Rolfe & Jason C. Crack & Debbie M. Hunt & Roger S. Buxton & Laura J. Smith & Nick E. Brun & Michael P. Williamson & Jeffrey Green, 2017. "Structure of a Wbl protein and implications for NO sensing by M. tuberculosis," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    2. Qiaozhi Wei & Sandra Pinho & Shuxian Dong & Halley Pierce & Huihui Li & Fumio Nakahara & Jianing Xu & Chunliang Xu & Philip E. Boulais & Dachuan Zhang & Maria Maryanovich & Ana Maria Cuervo & Paul S. , 2021. "MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Jin Kyung Kim & Yi Sak Kim & Hye-Mi Lee & Hyo Sun Jin & Chiranjivi Neupane & Sup Kim & Sang-Hee Lee & Jung-Joon Min & Miwa Sasai & Jae-Ho Jeong & Seong-Kyu Choe & Jin-Man Kim & Masahiro Yamamoto & Hyo, 2018. "GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
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