EsxH Inhibits ESCRT

Over 40 years ago, D’Arcy Hart showed that Mtb avoids delivery to lysosomes, but the molecular mechanisms that allow Mtb to elude lysosomal degradation remain poorly understood. Mtb has been reported to block MHC class II (MHC-II) antigen presentation, however the bacterial effectors and host cell targets mediating this effect are unknown. We found that the bacterial effector EsxH impairs both phagosome maturation and antigen presentation by targeting the host ESCRT machinery.

Specialized secretion systems are often used by bacterial pathogens to translocate effectors that target the host. Mtb encodes type VII secretion systems (T7SSs). The Esx-3 T7SS secretes the EsxG and EsxH heterodimer. EsxG-EsxH play a role in allowing the bacteria to acquire iron and zinc, essential elements for bacterial survival. They also play an important role in virulence that is distinct from their role in metal homeostasis. We found that EsxH interacts with the host hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), a component of the endosomal sorting complex required for transport (ESCRT). ESCRT has a well-described role in directing proteins destined for lysosomal degradation into multivesicular bodies, ensuring degradation of the sorted cargo upon lysosome fusion. We found that ESCRT is also required to deliver Mtb to the lysosome and to restrict intracellular bacterial growth. Thus, in addition to its intrinsic bacterial role in metal homeostasis, we showed that Mtb EsxH, in complex with EsxG, targets host ESCRT to prevent maturation of the Mtb phagosome. Thus, the ability of EsxGH to inhibit the ESCRT machinery underlies one of the central features of tuberculosis pathogenesis. Recently, we found that EsxH also inhibits antigen presentation. Thus, the ability of EsxGH to inhibit ESCRT also provides a molecular explanation for how Mtb undermines effector T cells responses.

Read more about our work on EsxH and ESCRT:

Portal-Celhay C, Tufariello JM, Srivastava S, Mehra A, Zahra A, Bean AJ, Ernst JD, Jacobs Jr. WR*, Philips JA.* Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent MHC class II antigen presentation, Nature Microbiol 2016: 2, 16232. (*equal contribution)

     Featured in Neyrolles, O. Bacterial Pathogenesis: A sand grain in antigen processing. Nature Microbiol 2016: 2, 16234. PMID: 27918496

     See Behind The Paper, Portal-Celhay C. The route towards T cell activation: how TB and I crossed paths: https://naturemicrobiologycommunity.nature.com/users/24403-cynthia-portal-celhay/posts/13820-the-route-towards-t-cell-activation-how-tb-and-i-crossed-paths

Tinaztepe E, Wei J-R, Raynowska J, Portal-Celhay C, Thompson V, and Philips, JA. The role of metal dependent regulation of ESX-3 secretion on the intracellular survival of Mycobacterium tuberculosis, Infect Immun 2016; May 31, pii: IAI00197-16 [Epub ahead of print]; PMID:27245412.

Tufariello JM, Chapman JR, Kerantzas CA, Wong KW, Vilchèze C, Jones CM, Cole LE, Tinaztepe E, Thompson V, Fenyö D, Niederweis M, Ueberheide B, Philips JA*, Jacobs WR Jr*. Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E348-57; (*equal contribution)

Mehra A*, Zahra A*, Thompson V, Sirisaengtaksin N, Wells A, Porto M, Koster, S, Penberthy K, Kubota Y, Dricot A, Rogan D, Vidal M, Hill DE, Bean AJ, Philips JA. Mycobacterium tuberculosis Type VII secreted effector EsxH targets host ESCRT to impair trafficking. PLOS Pathogens. 2013 Oct;9(10):e1003734. PMID 24204276; * equal contribution. doi: 10.1371/journal.ppat.1003734.