RT Journal Article
SR Electronic
T1 Plasma membrane damage causes NLRP3 activation and pyroptosis during <em>Mycobacterium tuberculosis</em> infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 747014
DO 10.1101/747014
A1 Beckwith, Kai S.
A1 Beckwith, Marianne S.
A1 Ullmann, Sindre
A1 Sætra, Ragnhild
A1 Kim, Haelin
A1 Marstad, Anne
A1 Åsberg, Signe E.
A1 Strand, Trine A.
A1 Stenmark, Harald A.
A1 Flo, Trude H.
YR 2019
UL http://biorxiv.org/content/early/2019/08/28/747014.abstract
AB Mycobacterium tuberculosis (Mtb) is a major global health problem and causes extensive cytotoxicity in patient cells and tissues. Here we define an NLRP3, caspase-1 and gasdermin D-mediated pathway to pyroptosis in human monocytes following exposure to Mtb. We demonstrate an ESX-1 mediated, contact-induced plasma membrane (PM) damage response that occurs during phagocytosis or from the cytosolic side of the PM after phagosomal rupture in Mtb infected cells. This PM injury in turn causes K+ efflux and activation of NLRP3 dependent IL-1β release and pyroptosis, facilitating the spread of Mtb to neighbouring cells. Further we reveal a dynamic interplay of pyroptosis with ESCRT-mediated PM repair. Collectively, these findings reveal a novel mechanism for pyroptosis and spread of infection acting through dual PM disturbances both during and after phagocytosis. We also highlight dual PM damage as a common mechanism utilized by other NLRP3 activators that have previously been shown to act through lysosomal damage.