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Review
. 2023 May 4;19(5):e1011344.
doi: 10.1371/journal.ppat.1011344. eCollection 2023 May.

The multifaceted interactions between pathogens and host ESCRT machinery

Yolanda Rivera-Cuevas  1 , Vern B Carruthers  1
Affiliations
Review

The multifaceted interactions between pathogens and host ESCRT machinery

Yolanda Rivera-Cuevas et al. PLoS Pathog. .

Abstract

The Endosomal Sorting Complex Required for Transport (ESCRT) machinery consists of multiple protein complexes that coordinate vesicle budding away from the host cytosol. ESCRTs function in many fundamental cellular processes including the biogenesis of multivesicular bodies and exosomes, membrane repair and restoration, and cell abscission during cytokinesis. Work over the past 2 decades has shown that a diverse cohort of viruses critically rely upon host ESCRT machinery for virus replication and envelopment. More recent studies reported that intracellular bacteria and the intracellular parasite Toxoplasma gondii benefit from, antagonize, or exploit host ESCRT machinery to preserve their intracellular niche, gain resources, or egress from infected cells. Here, we review how intracellular pathogens interact with the ESCRT machinery of their hosts, highlighting the variety of strategies they use to bind ESCRT complexes using short linear amino acid motifs like those used by ESCRTs to sequentially assemble on target membranes. Future work exposing new mechanisms of this molecular mimicry will yield novel insight of how pathogens exploit host ESCRT machinery and how ESCRTs facilitate key cellular processes.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. The role of plant ESCRTs in microbial infection.
Plant viruses make use of the host ESCRT machinery for the formation of VRCs at different host organelles: (1) TBSV at peroxisomes via the viral protein p33 encoding a P[S/T]AP-like late domain motif; (2) BMV at the mitochondria via the viral protein 1a N-terminus; and (3) CIRV at the ER. (4) Plant ESCRTs also contribute to the formation of EVs that are secreted in response to pathogens as a mechanism for intrinsic defense. Created using Biorender.com. BMV, brome mosaic virus; CIRV, carnation Italian ringspot virus; ER, endoplasmic reticulum; ESCRT, Endosomal Sorting Complex Required for Transport; EV, extracellular vesicle; TBSV, Tomato bushy stunt virus; VRC, viral replication complex.
Fig 2
Fig 2. Mechanisms of ESCRT exploitation by RNA viruses.
(1) Retroviruses, such as the HIV-1, interact with the host ESCRT machinery for viral budding via structural proteins like Gag, encoding the P[S/T]AP and YPXL late domain motifs. Other RNA viruses like (2) DENV and (3) HCV recruit host ESCRT components to the ER to promote viral replication. This recruitment is facilitated by nonstructural proteins (NS) via unknown mechanisms. Created using Biorender.com. DENV, dengue virus; ER, endoplasmic reticulum; ESCRT, Endosomal Sorting Complex Required for Transport; HCV, hepatitis C virus; HIV-1, human immunodeficiency virus-1.
Fig 3
Fig 3. Mechanisms of ESCRT exploitation by DNA viruses.
(1) The DNA virus HSV-1 requires ESCRT components for (1a) primary envelopment at the nucleus via the arginine-rich cluster at the UL34 viral protein and (1b) secondary envelopment at the trans-Golgi via the P[S/T]AP and YPXL late domain motifs encoded by UL36. (2) VACV recruits the ESCRT machinery for viral envelopment and egress from MVBs. The viral protein F13L has been proposed to interact with ESCRT components via YPXL late domain motifs. Created using Biorender.com. ESCRT, Endosomal Sorting Complex Required for Transport; HSV-1, herpes simplex virus-1; MVB, multivesicular body; VACV, vaccinia virus.
Fig 4
Fig 4. The host ESCRT machinery and nonviral pathogens.
The outcome of intracellular bacterial infection is affected by the host ESCRT machinery. (1) Brucella abortus recruits ESCRT components to its PVC, which resembles an MVB, to promote proliferation and release. (2) Salmonella spp. recruit ESCRT components for the formation of its PCV. The bacterial protein SpoB has been proposed to mediate this interaction. (3) Differently from A. phagocytophilum and Salmonella, Mycobacterium tuberculosis inhibits the function of the host ESCRT machinery to evade clearance and promote its survival. The bacteria secrete the effector proteins EsxG and EsxH to inhibit ESCRT-dependent PCV repair (4) The UPEC are encased in MVBs by the host ESCRT machinery for expulsion from cells, a mechanism for ESCRT-mediated intrinsic defense. Created using Biorender.com. ESCRT, Endosomal Sorting Complex Required for Transport; MVB, multivesicular body; PVC, pathogen-containing vacuole; UPEC, uropathogenic Escherichia coli.
Fig 5
Fig 5. gondii has different strategies for exploiting the host ESCRT machinery.
T. (1) The protozoan parasite Toxoplasma gondii recruits the early ESCRT components TSG101 and ALIX during invasion via the P[S/T]AP and YPXL late domain motifs encoded by RON5 and RON2, respectively. (2) While residing in its replicative compartment known as the PV, the parasite recruits ESCRT components for the uptake of resources from the host cell across the PV membrane. (2a) GRA14 encodes both P[S/T]AP and YPXL late domain motifs and is required for the recruitment of the host ESCRT machinery for the uptake of host cytosolic proteins. (2b) Additionally, GRA14 alongside another parasite ESCRT-interacting protein GRA64, are necessary for the sequestration of host vesicles. Created using Biorender.com. ESCRT, Endosomal Sorting Complex Required for Transport; PV, parasitophorous vacuole.
Fig 6
Fig 6. A pathogen’s guide for exploiting the host ESCRT machinery.
ESCRT are involved in multiple functions in cells and many intracellular pathogens have evolved ways to exploit ESCRTs for key aspects of their pathogenesis. Viral envelopment and budding: For viral envelopment and budding, viruses encode short linear amino acid motifs that mimic ESCRT interactions necessary for ESCRTs sequentially assemble. Viral replication: Alternatively, viruses can recruit host ESCRT components for the formation of replication complexes at host organelles. These strategies used by RNA and DNA viruses resemble MVB formation by ESCRT. Bacterial survival, maintenance of replicative compartment, and release: Bacteria can also benefit from the host ESCRT machinery for the biogenesis, maintenance (ESCRT membrane repair function), and release of their replicative compartment (ESCRT MVB formation and exosome release). Parasite invasion and resource acquisition: The protozoan parasite Toxoplasma gondii recruits early ESCRT components for invasion and subsequently during replication for resource acquisition. Intrinsic defense: Interestingly, the role of ESCRT has also been associated with intrinsic defenses against pathogens, for example, expulsion of infecting bacteria and enclosing foreign DNA in exosomes for immune signalling. Created using Biorender.com. ESCRT, Endosomal Sorting Complex Required for Transport; MVB, multivesicular body.
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