A TRAF-like E3 ubiquitin ligase TrafE coordinates ESCRT and autophagy in endolysosomal damage response and cell-autonomous immunity to Mycobacterium marinum
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eLife assessment
This study presents important findings on the mechanism as to how Mycobacterium-containing vacuoles are recognized by host cell factors and subjected to membrane repair or autophagic degradation using Dictyostelium discoideum as a useful model. The evidence for the role of TrafE in damaged-membrane repair and xenophagy induction is convincing, but that in autophagosome closure is rather incomplete.
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Abstract
Cells are perpetually challenged by pathogens, protein aggregates or chemicals, that induce plasma membrane or endolysosomal compartments damage. This severe stress is recognised and controlled by the endosomal sorting complex required for transport (ESCRT) and the autophagy machineries, which are recruited to damaged membranes to either repair or to remove membrane remnants. Yet, insight is limited about how damage is sensed and which effectors lead to extensive tagging of the damaged organelles with signals, such as K63-polyubiquitin, required for the recruitment of membrane repair or removal machineries. To explore the key factors responsible for detection and marking of damaged compartments, we use the professional phagocyte Dictyostelium discoideum . We found an evolutionary conserved E3-ligase, TrafE, that is robustly recruited to intracellular compartments disrupted after infection with Mycobacterium marinum or after sterile damage caused by chemical compounds. TrafE acts at the intersection of ESCRT and autophagy pathways and plays a key role in functional recruitment of the ESCRT subunits ALIX, Vps32 and Vps4 to damage sites. Importantly, we show that the absence of TrafE severely compromises the xenophagy restriction of mycobacteria as well as ESCRT-mediated and autophagy-mediated endolysosomal membrane damage repair, resulting in early cell death.
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eLife assessment
This study presents important findings on the mechanism as to how Mycobacterium-containing vacuoles are recognized by host cell factors and subjected to membrane repair or autophagic degradation using Dictyostelium discoideum as a useful model. The evidence for the role of TrafE in damaged-membrane repair and xenophagy induction is convincing, but that in autophagosome closure is rather incomplete.
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Reviewer #1 (Public Review):
The authors show that TrafE, which is one of the five Dictyostelium discoideum TRAF proteins, is recruited to the Mycobacterium-containing vacuoles (MCVs) and is required for membrane damage repair and xenophagy. They propose that the TrafE-Ub-ALIX axis is important for the regulation of Vps4, and, thereby, for the normal function of ESCRT. They also suggest that TrafE is involved in phagophore sealing.
Overall, the parts of membrane damage repair and xenophagy induction are convincing. Although mammalian TRAF6 was already reported to be involved in the ubiquitination of Chlamydia and Toxoplasma-containing vacuoles (Haldar et al. PNAS, 2015, https://www.pnas.org/doi/epdf/10.1073/pnas.1515966112), how TRAF6 is recruited to pathogen-containing vacuoles remained unknown. This study reveals that the recruitment …
Reviewer #1 (Public Review):
The authors show that TrafE, which is one of the five Dictyostelium discoideum TRAF proteins, is recruited to the Mycobacterium-containing vacuoles (MCVs) and is required for membrane damage repair and xenophagy. They propose that the TrafE-Ub-ALIX axis is important for the regulation of Vps4, and, thereby, for the normal function of ESCRT. They also suggest that TrafE is involved in phagophore sealing.
Overall, the parts of membrane damage repair and xenophagy induction are convincing. Although mammalian TRAF6 was already reported to be involved in the ubiquitination of Chlamydia and Toxoplasma-containing vacuoles (Haldar et al. PNAS, 2015, https://www.pnas.org/doi/epdf/10.1073/pnas.1515966112), how TRAF6 is recruited to pathogen-containing vacuoles remained unknown. This study reveals that the recruitment of TrafE to MCVs is dependent on membrane damage or reduced membrane tension. This is novel. However, the part of phagophore closure is too preliminary. The evidence that TrafE is involved in the phagophore closure is mostly indirect and weak.
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Reviewer #2 (Public Review):
Raykov et al. reported that TrafE, a member of the E3 ubiquitin ligase family similar to the TRAF proteins in mammalian cells, is essential for Dictyostelium discoideum to effectively respond to endolysosomal damage and defend itself against Mycobacterium marinum infection. First, the authors demonstrate that TrafE is recruited to the site of Mycobacterium-Containing Vacuole (MCV) damage along with ubiquitin molecules. This recruitment is necessary for the effective suppression of M. marinum growth in the cells. They also found that this response was not limited to the damage caused by M. marinum, but was also triggered by sterile damage caused by chemical compounds. Furthermore, the authors revealed that TrafE plays a role in the recruitment of Vps4 to sites of membrane damage and regulates the disassembly …
Reviewer #2 (Public Review):
Raykov et al. reported that TrafE, a member of the E3 ubiquitin ligase family similar to the TRAF proteins in mammalian cells, is essential for Dictyostelium discoideum to effectively respond to endolysosomal damage and defend itself against Mycobacterium marinum infection. First, the authors demonstrate that TrafE is recruited to the site of Mycobacterium-Containing Vacuole (MCV) damage along with ubiquitin molecules. This recruitment is necessary for the effective suppression of M. marinum growth in the cells. They also found that this response was not limited to the damage caused by M. marinum, but was also triggered by sterile damage caused by chemical compounds. Furthermore, the authors revealed that TrafE plays a role in the recruitment of Vps4 to sites of membrane damage and regulates the disassembly of ESCRT subunits. While TRAF6 has been previously implicated in ubiquitination in response to invaded bacteria in mammalian cells, this study provides solid data that furthers our understanding of the mechanism behind xenophagy. The authors conducted a thorough analysis to contribute to this field of research.
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