PMID- 36248815 OWN - NLM STAT- MEDLINE DCOM- 20221018 LR - 20221020 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Mycobacterial acyl carrier protein suppresses TFEB activation and upregulates miR-155 to inhibit host defense. PG - 946929 LID - 10.3389/fimmu.2022.946929 [doi] LID - 946929 AB - Mycobacterial acyl carrier protein (AcpM; Rv2244), a key protein involved in Mycobacterium tuberculosis (Mtb) mycolic acid production, has been shown to suppress host cell death during mycobacterial infection. This study reports that mycobacterial AcpM works as an effector to subvert host defense and promote bacterial growth by increasing microRNA (miRNA)-155-5p expression. In murine bone marrow-derived macrophages (BMDMs), AcpM protein prevented transcription factor EB (TFEB) from translocating to the nucleus in BMDMs, which likely inhibited transcriptional activation of several autophagy and lysosomal genes. Although AcpM did not suppress autophagic flux in BMDMs, AcpM reduced Mtb and LAMP1 co-localization indicating that AcpM inhibits phagolysosomal fusion during Mtb infection. Mechanistically, AcpM boosted the Akt-mTOR pathway in BMDMs by upregulating miRNA-155-5p, a SHIP1-targeting miRNA. When miRNA-155-5p expression was inhibited in BMDMs, AcpM-induced increased intracellular survival of Mtb was suppressed. In addition, AcpM overexpression significantly reduced mycobacterial clearance in C3HeB/FeJ mice infected with recombinant M. smegmatis strains. Collectively, our findings point to AcpM as a novel mycobacterial effector to regulate antimicrobial host defense and a potential new therapeutic target for Mtb infection. CI - Copyright (c) 2022 Paik, Kim, Kim, Kim, Kim, Choi, Kim and Jo. FAU - Paik, Seungwha AU - Paik S AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. FAU - Kim, Kyeong Tae AU - Kim KT AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, South Korea. FAU - Kim, In Soo AU - Kim IS AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, South Korea. FAU - Kim, Young Jae AU - Kim YJ AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, South Korea. FAU - Kim, Hyeon Ji AU - Kim HJ AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, South Korea. FAU - Choi, Seunga AU - Choi S AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. FAU - Kim, Hwa-Jung AU - Kim HJ AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, South Korea. FAU - Jo, Eun-Kyeong AU - Jo EK AD - Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. AD - Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, South Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220928 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Acyl Carrier Protein) RN - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) RN - 0 (MicroRNAs) RN - 0 (Mirn155 microRNA, mouse) RN - 0 (Mycolic Acids) RN - 0 (Tcfeb protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Acyl Carrier Protein MH - Animals MH - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism MH - Mice MH - *MicroRNAs/genetics/metabolism MH - *Mycobacterium tuberculosis/physiology MH - Mycolic Acids MH - Proto-Oncogene Proteins c-akt/metabolism MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC9559204 OTO - NOTNLM OT - Mycobacterium tuberculosis OT - acyl carrier protein OT - bone marrow-derived macrophages OT - microRNA-155-5p OT - phagosome-lysosome fusion OT - transcription factor EB COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/10/18 06:00 MHDA- 2022/10/19 06:00 PMCR- 2022/01/01 CRDT- 2022/10/17 05:13 PHST- 2022/05/18 00:00 [received] PHST- 2022/09/07 00:00 [accepted] PHST- 2022/10/17 05:13 [entrez] PHST- 2022/10/18 06:00 [pubmed] PHST- 2022/10/19 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.946929 [doi] PST - epublish SO - Front Immunol. 2022 Sep 28;13:946929. doi: 10.3389/fimmu.2022.946929. eCollection 2022.