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The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella typhimurium by autophagy

The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella typhimurium by autophagy
The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella typhimurium by autophagy
Autophagy plays a key role during Salmonella infection, by eliminating these pathogens following escape into the cytosol. In this process, selective autophagy receptors, including the myosin VI adaptor proteins optineurin and NDP52, have been shown to recognize cytosolic pathogens. Here, we demonstrate that myosin VI and TAX1BP1 are recruited to ubiquitylated Salmonella and play a key role in xenophagy. The absence of TAX1BP1 causes an accumulation of ubiquitin-positive Salmonella, whereas loss of myosin VI leads to an increase in ubiquitylated and LC3-positive bacteria. Our structural studies demonstrate that the ubiquitin-binding site of TAX1BP1 overlaps with the myosin VI binding site and point mutations in the TAX1BP1 zinc finger domains that affect ubiquitin binding also ablate binding to myosin VI. This mutually exclusive binding and the association of TAX1BP1 with LC3 on the outer limiting membrane of autophagosomes may suggest a molecular mechanism for recruitment of this motor to autophagosomes. The predominant role of TAX1BP1, a paralogue of NDP52, in xenophagy is supported by our evolutionary analysis, which demonstrates that functionally intact NDP52 is missing in Xenopus and mice, whereas TAX1BP1 is expressed in all vertebrates analysed. In summary, this work highlights the importance of TAX1BP1 as a novel autophagy receptor in myosin VI-mediated xenophagy. Our study identifies essential new machinery for the autophagy-dependent clearance of Salmonella typhimurium and suggests modulation of myosin VI motor activity as a potential therapeutic target in cellular immunity.
1553-7366
1-26
Tumbarello, David A.
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Manna, Paul T.
eb0f7d8c-6f9d-418e-826c-5ada11611d53
Allen, Mark
f200a4d3-e0b7-4f7d-a095-749afd52c415
Bycroft, Mark
a0aca934-e6d5-43b5-87c0-a2d3de110d7f
Arden, Susan D.
47286333-3c42-4c14-ac71-14c5b7ac4e61
Kendrick-Jones, John
0c756304-5044-44a0-8277-0e8b352b8aae
Buss, Folma
f8b3fde3-6724-4412-aa65-674cbfb73121
Tumbarello, David A.
75c6932e-fdbf-4d3c-bb4f-48fbbdba93a2
Manna, Paul T.
eb0f7d8c-6f9d-418e-826c-5ada11611d53
Allen, Mark
f200a4d3-e0b7-4f7d-a095-749afd52c415
Bycroft, Mark
a0aca934-e6d5-43b5-87c0-a2d3de110d7f
Arden, Susan D.
47286333-3c42-4c14-ac71-14c5b7ac4e61
Kendrick-Jones, John
0c756304-5044-44a0-8277-0e8b352b8aae
Buss, Folma
f8b3fde3-6724-4412-aa65-674cbfb73121

Tumbarello, David A., Manna, Paul T., Allen, Mark, Bycroft, Mark, Arden, Susan D., Kendrick-Jones, John and Buss, Folma (2015) The autophagy receptor TAX1BP1 and the molecular motor myosin VI are required for clearance of Salmonella typhimurium by autophagy. PLOS Pathogens, 11 (10), 1-26, [e1005174]. (doi:10.1371/journal.ppat.1005174). (PMID:26451915)

Record type: Article

Abstract

Autophagy plays a key role during Salmonella infection, by eliminating these pathogens following escape into the cytosol. In this process, selective autophagy receptors, including the myosin VI adaptor proteins optineurin and NDP52, have been shown to recognize cytosolic pathogens. Here, we demonstrate that myosin VI and TAX1BP1 are recruited to ubiquitylated Salmonella and play a key role in xenophagy. The absence of TAX1BP1 causes an accumulation of ubiquitin-positive Salmonella, whereas loss of myosin VI leads to an increase in ubiquitylated and LC3-positive bacteria. Our structural studies demonstrate that the ubiquitin-binding site of TAX1BP1 overlaps with the myosin VI binding site and point mutations in the TAX1BP1 zinc finger domains that affect ubiquitin binding also ablate binding to myosin VI. This mutually exclusive binding and the association of TAX1BP1 with LC3 on the outer limiting membrane of autophagosomes may suggest a molecular mechanism for recruitment of this motor to autophagosomes. The predominant role of TAX1BP1, a paralogue of NDP52, in xenophagy is supported by our evolutionary analysis, which demonstrates that functionally intact NDP52 is missing in Xenopus and mice, whereas TAX1BP1 is expressed in all vertebrates analysed. In summary, this work highlights the importance of TAX1BP1 as a novel autophagy receptor in myosin VI-mediated xenophagy. Our study identifies essential new machinery for the autophagy-dependent clearance of Salmonella typhimurium and suggests modulation of myosin VI motor activity as a potential therapeutic target in cellular immunity.

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Accepted/In Press date: 28 August 2015
e-pub ahead of print date: 9 October 2015
Organisations: Molecular and Cellular

Identifiers

Local EPrints ID: 382846
URI: http://eprints.soton.ac.uk/id/eprint/382846
ISSN: 1553-7366
PURE UUID: bed5083c-1f65-4715-bfca-6774c93ca8c8
ORCID for David A. Tumbarello: ORCID iD orcid.org/0000-0002-5169-0561

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Date deposited: 03 Nov 2015 15:27
Last modified: 15 Mar 2024 03:50

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Contributors

Author: Paul T. Manna
Author: Mark Allen
Author: Mark Bycroft
Author: Susan D. Arden
Author: John Kendrick-Jones
Author: Folma Buss

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