Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages

ABSTRACT Mycobacterium tuberculosis (Mtb) causes one of the deadliest infectious diseases worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell. We showed previously that the ESX-1 secretion system perturbs th...

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Autores principales: Samantha L. Bell, Kayla L. Lopez, Jeffery S. Cox, Kristin L. Patrick, Robert O. Watson
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Publicado: American Society for Microbiology 2021
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spelling oai:doaj.org-article:adcda7fd76914fb3b611f58e30465cdc2021-11-10T18:37:52ZGalectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages10.1128/mBio.01871-202150-7511https://doaj.org/article/adcda7fd76914fb3b611f58e30465cdc2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01871-20https://doaj.org/toc/2150-7511ABSTRACT Mycobacterium tuberculosis (Mtb) causes one of the deadliest infectious diseases worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell. We showed previously that the ESX-1 secretion system perturbs the Mtb-containing phagosome, and a population (∼30%) of intracellular Mtb is tagged with ubiquitin and targeted to selective autophagy. However, our understanding of how macrophages sense and respond to damaged Mtb-containing phagosomes remains incomplete. Here, we demonstrate that several cytosolic glycan-binding proteins called galectins recognize Mtb-containing phagosomes; in macrophage cell lines and in primary macrophages, galectin-3, -8, and -9 are all recruited to the same Mtb population that colocalizes with selective autophagy markers (ubiquitin, p62, and LC3). To test whether galectins are required for controlling Mtb replication in macrophages, we generated CRISPR/Cas9 knockouts and found that galectin-8−/− and galectin-3/8/9−/− macrophages were similarly defective in targeting Mtb to selective autophagy and controlling replication. This suggests galectin-8 plays a unique role in anti-Mtb autophagy. In investigating galectin-8's role, we identified a novel and specific interaction between galectin-8 and the selective autophagy adapter TAX1BP1 and found that this galectin-8/TAX1BP1 interaction was necessary for macrophages to efficiently target Mtb to selective autophagy. Remarkably, overexpressing galectin-8 increased targeting of Mtb to autophagy and limited Mtb replication. Taken together, these data demonstrate that while several galectins are capable of recognizing damaged Mtb-containing phagosomes, galectin-8 plays a privileged role in recruiting downstream autophagy machinery and may represent a promising target for host-directed tuberculosis therapies. IMPORTANCE Mycobacterium tuberculosis (Mtb) infects one-quarter of the global population and causes one of the deadliest infectious diseases worldwide. Macrophages are the first line of defense against Mtb infection and are typically incredibly efficient at destroying intracellular pathogens, but Mtb has evolved to survive and replicate in this harsh environment. Previous work has found that a portion of intracellular Mtb bacilli damage their phagosomes, leaving them vulnerable to detection by the host and delivery to an antibacterial pathway called selective autophagy. Here, we show that in macrophages, galectin-8 recognizes damaged Mtb-containing phagosomes and targets Mtb to selective autophagy; we found that galectin-8, unlike other highly similar and closely related galectins, is required for targeting and controlling Mtb in macrophages. The specific role for galectin-8 appears to stem from its interaction with TAX1BP1, a selective autophagy adapter protein. Interestingly, overexpressing galectin-8 helps macrophages target and control Mtb, highlighting the importance of galectin-8 in the innate immune response to Mtb.Samantha L. BellKayla L. LopezJeffery S. CoxKristin L. PatrickRobert O. WatsonAmerican Society for Microbiologyarticlexenophagybacterial pathogenesishost-pathogen interactionsinnate immunityMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution DOAJ
collection DOAJ
language EN
topic xenophagy
bacterial pathogenesis
host-pathogen interactions
innate immunity
Microbiology
QR1-502
spellingShingle xenophagy
bacterial pathogenesis
host-pathogen interactions
innate immunity
Microbiology
QR1-502
Samantha L. Bell
Kayla L. Lopez
Jeffery S. Cox
Kristin L. Patrick
Robert O. Watson
Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages
description ABSTRACT Mycobacterium tuberculosis (Mtb) causes one of the deadliest infectious diseases worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell. We showed previously that the ESX-1 secretion system perturbs the Mtb-containing phagosome, and a population (∼30%) of intracellular Mtb is tagged with ubiquitin and targeted to selective autophagy. However, our understanding of how macrophages sense and respond to damaged Mtb-containing phagosomes remains incomplete. Here, we demonstrate that several cytosolic glycan-binding proteins called galectins recognize Mtb-containing phagosomes; in macrophage cell lines and in primary macrophages, galectin-3, -8, and -9 are all recruited to the same Mtb population that colocalizes with selective autophagy markers (ubiquitin, p62, and LC3). To test whether galectins are required for controlling Mtb replication in macrophages, we generated CRISPR/Cas9 knockouts and found that galectin-8−/− and galectin-3/8/9−/− macrophages were similarly defective in targeting Mtb to selective autophagy and controlling replication. This suggests galectin-8 plays a unique role in anti-Mtb autophagy. In investigating galectin-8's role, we identified a novel and specific interaction between galectin-8 and the selective autophagy adapter TAX1BP1 and found that this galectin-8/TAX1BP1 interaction was necessary for macrophages to efficiently target Mtb to selective autophagy. Remarkably, overexpressing galectin-8 increased targeting of Mtb to autophagy and limited Mtb replication. Taken together, these data demonstrate that while several galectins are capable of recognizing damaged Mtb-containing phagosomes, galectin-8 plays a privileged role in recruiting downstream autophagy machinery and may represent a promising target for host-directed tuberculosis therapies. IMPORTANCE Mycobacterium tuberculosis (Mtb) infects one-quarter of the global population and causes one of the deadliest infectious diseases worldwide. Macrophages are the first line of defense against Mtb infection and are typically incredibly efficient at destroying intracellular pathogens, but Mtb has evolved to survive and replicate in this harsh environment. Previous work has found that a portion of intracellular Mtb bacilli damage their phagosomes, leaving them vulnerable to detection by the host and delivery to an antibacterial pathway called selective autophagy. Here, we show that in macrophages, galectin-8 recognizes damaged Mtb-containing phagosomes and targets Mtb to selective autophagy; we found that galectin-8, unlike other highly similar and closely related galectins, is required for targeting and controlling Mtb in macrophages. The specific role for galectin-8 appears to stem from its interaction with TAX1BP1, a selective autophagy adapter protein. Interestingly, overexpressing galectin-8 helps macrophages target and control Mtb, highlighting the importance of galectin-8 in the innate immune response to Mtb.
format article
author Samantha L. Bell
Kayla L. Lopez
Jeffery S. Cox
Kristin L. Patrick
Robert O. Watson
author_facet Samantha L. Bell
Kayla L. Lopez
Jeffery S. Cox
Kristin L. Patrick
Robert O. Watson
author_sort Samantha L. Bell
title Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages
title_short Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages
title_full Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages
title_fullStr Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages
title_full_unstemmed Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control <italic toggle="yes">Mycobacterium tuberculosis</italic> Infection in Macrophages
title_sort galectin-8 senses phagosomal damage and recruits selective autophagy adapter tax1bp1 to control <italic toggle="yes">mycobacterium tuberculosis</italic> infection in macrophages
publisher American Society for Microbiology
publishDate 2021
url https://doaj.org/article/adcda7fd76914fb3b611f58e30465cdc
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