biostudies-literatureLagune MMukoviszidose Institut gGmbHLabex EpiGenMedGerman Cystic Fibrosis Association Mukoviszidose e.V.Horizon 2020Joachim Herz StiftungGrégory Lemarchal AssociationAssociation Vaincre la Mucoviscidosee1010771https://www.ebi.ac.uk/biostudies/studies/S-EPMC9401124biostudies-literatureUnknown18(8)ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT delePLoS pathogensThe ESX-4 substrates, EsxU and EsxT, modulate Mycobacterium abscessus fitness.PMC9401124ANR-10-LABX-12-01Marie Skłodowska-Curie grant agreement no 846476grant agreement n°RIF20190502522Maurer FPWilmanns MVasquez Sotomayor FHerrmann JLPetit CCosentino GKremer LPaulowski LGutsmann TLe Moigne VJohansen MDGirard-Misguich FDaher WLagune MfalseThe ESX-4 substrates, EsxU and EsxT, modulate Mycobacterium abscessus fitness.ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT dele2022-01-01T00:00:00Z2022 Aug2026-06-01T02:20:29.005Z2025-04-19T09:30:27.029ZS-EPMC94011243596076610.1371/journal.ppat.1010771