<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity

ABSTRACT Mycoplasma pneumoniae is an atypical bacterium that causes respiratory illnesses in humans, including pharyngitis, tracheobronchitis, and community-acquired pneumonia (CAP). It has also been directly linked to reactive airway disease, asthma, and extrapulmonary pathologies. During its colon...

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Autores principales:	Kumaraguruparan Ramasamy, Sowmya Balasubramanian, Krishnan Manickam, Lavanya Pandranki, Alexander B. Taylor, P. John Hart, Joel B. Baseman, T. R. Kannan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	CARDS toxin KDEL KELED Mycoplasma retrograde transport vacuolation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/489935ccd5df4999aa84dba51dd4172e
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spelling	oai:doaj.org-article:489935ccd5df4999aa84dba51dd4172e2021-11-15T15:53:25Z<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity10.1128/mBio.01663-172150-7511https://doaj.org/article/489935ccd5df4999aa84dba51dd4172e2018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01663-17https://doaj.org/toc/2150-7511ABSTRACT Mycoplasma pneumoniae is an atypical bacterium that causes respiratory illnesses in humans, including pharyngitis, tracheobronchitis, and community-acquired pneumonia (CAP). It has also been directly linked to reactive airway disease, asthma, and extrapulmonary pathologies. During its colonization, M. pneumoniae expresses a unique ADP-ribosylating and vacuolating cytotoxin designated community-acquired respiratory distress syndrome (CARDS) toxin. CARDS toxin persists and localizes in the airway in CAP patients, asthmatics, and trauma patients with ventilator-associated pneumonia. Although CARDS toxin binds to specific cellular receptors, is internalized, and induces hyperinflammation, histopathology, mucus hyperplasia, and other airway injury, the intracellular trafficking of CARDS toxin remains unclear. Here, we show that CARDS toxin translocates through early and late endosomes and the Golgi complex and concentrates at the perinuclear region to reach the endoplasmic reticulum (ER). Using ER-targeted SNAP-tag, we confirmed the association of CARDS toxin with the ER and determined that CARDS toxin follows the retrograde pathway. In addition, we identified a novel CARDS toxin amino acid fingerprint, KELED, that is required for toxin transport to the ER and subsequent toxin-mediated cytotoxicity. IMPORTANCE Mycoplasma pneumoniae, a leading cause of bacterial community-acquired pneumonia (CAP) among children and adults in the United States, synthesizes a 591-amino-acid ADP-ribosylating and vacuolating protein, designated community-acquired respiratory distress syndrome (CARDS) toxin. CARDS toxin alone is sufficient to induce and mimic major inflammatory and histopathological phenotypes associated with M. pneumoniae infection in rodents and primates. In order to elicit its ADP-ribosylating and vacuolating activities, CARDS toxin must bind to host cell receptors, be internalized via clathrin-mediated pathways, and subsequently be transported to specific intracellular organelles. Here, we demonstrate how CARDS toxin utilizes its unique KELED sequence to exploit the retrograde pathway machinery to reach the endoplasmic reticulum (ER) and fulfill its cytopathic potential. The knowledge generated from these studies may provide important clues to understand the mode of action of CARDS toxin and develop interventions that reduce or eliminate M. pneumoniae-associated airway and extrapulmonary pathologies.Kumaraguruparan RamasamySowmya BalasubramanianKrishnan ManickamLavanya PandrankiAlexander B. TaylorP. John HartJoel B. BasemanT. R. KannanAmerican Society for MicrobiologyarticleCARDS toxinKDELKELEDMycoplasmaretrograde transportvacuolationMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	CARDS toxin KDEL KELED Mycoplasma retrograde transport vacuolation Microbiology QR1-502
spellingShingle	CARDS toxin KDEL KELED Mycoplasma retrograde transport vacuolation Microbiology QR1-502 Kumaraguruparan Ramasamy Sowmya Balasubramanian Krishnan Manickam Lavanya Pandranki Alexander B. Taylor P. John Hart Joel B. Baseman T. R. Kannan <italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity
description	ABSTRACT Mycoplasma pneumoniae is an atypical bacterium that causes respiratory illnesses in humans, including pharyngitis, tracheobronchitis, and community-acquired pneumonia (CAP). It has also been directly linked to reactive airway disease, asthma, and extrapulmonary pathologies. During its colonization, M. pneumoniae expresses a unique ADP-ribosylating and vacuolating cytotoxin designated community-acquired respiratory distress syndrome (CARDS) toxin. CARDS toxin persists and localizes in the airway in CAP patients, asthmatics, and trauma patients with ventilator-associated pneumonia. Although CARDS toxin binds to specific cellular receptors, is internalized, and induces hyperinflammation, histopathology, mucus hyperplasia, and other airway injury, the intracellular trafficking of CARDS toxin remains unclear. Here, we show that CARDS toxin translocates through early and late endosomes and the Golgi complex and concentrates at the perinuclear region to reach the endoplasmic reticulum (ER). Using ER-targeted SNAP-tag, we confirmed the association of CARDS toxin with the ER and determined that CARDS toxin follows the retrograde pathway. In addition, we identified a novel CARDS toxin amino acid fingerprint, KELED, that is required for toxin transport to the ER and subsequent toxin-mediated cytotoxicity. IMPORTANCE Mycoplasma pneumoniae, a leading cause of bacterial community-acquired pneumonia (CAP) among children and adults in the United States, synthesizes a 591-amino-acid ADP-ribosylating and vacuolating protein, designated community-acquired respiratory distress syndrome (CARDS) toxin. CARDS toxin alone is sufficient to induce and mimic major inflammatory and histopathological phenotypes associated with M. pneumoniae infection in rodents and primates. In order to elicit its ADP-ribosylating and vacuolating activities, CARDS toxin must bind to host cell receptors, be internalized via clathrin-mediated pathways, and subsequently be transported to specific intracellular organelles. Here, we demonstrate how CARDS toxin utilizes its unique KELED sequence to exploit the retrograde pathway machinery to reach the endoplasmic reticulum (ER) and fulfill its cytopathic potential. The knowledge generated from these studies may provide important clues to understand the mode of action of CARDS toxin and develop interventions that reduce or eliminate M. pneumoniae-associated airway and extrapulmonary pathologies.
format	article
author	Kumaraguruparan Ramasamy Sowmya Balasubramanian Krishnan Manickam Lavanya Pandranki Alexander B. Taylor P. John Hart Joel B. Baseman T. R. Kannan
author_facet	Kumaraguruparan Ramasamy Sowmya Balasubramanian Krishnan Manickam Lavanya Pandranki Alexander B. Taylor P. John Hart Joel B. Baseman T. R. Kannan
author_sort	Kumaraguruparan Ramasamy
title	<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity
title_short	<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity
title_full	<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity
title_fullStr	<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity
title_full_unstemmed	<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity
title_sort	<italic toggle="yes">mycoplasma pneumoniae</italic> community-acquired respiratory distress syndrome toxin uses a novel keled sequence for retrograde transport and subsequent cytotoxicity
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/489935ccd5df4999aa84dba51dd4172e
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<italic toggle="yes">Mycoplasma pneumoniae</italic> Community-Acquired Respiratory Distress Syndrome Toxin Uses a Novel KELED Sequence for Retrograde Transport and Subsequent Cytotoxicity

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