Date Published: June 7, 2019
Publisher: Public Library of Science
Author(s): Maria Kusmierek, Jörn Hoßmann, Rebekka Witte, Wiebke Opitz, Ines Vollmer, Marcel Volk, Ann Kathrin Heroven, Hans Wolf-Watz, Petra Dersch, Joan Mecsas.
Numerous Gram-negative pathogens use a Type III Secretion System (T3SS) to promote virulence by injecting effector proteins into targeted host cells, which subvert host cell processes. Expression of T3SS and the effectors is triggered upon host cell contact, but the underlying mechanism is poorly understood. Here, we report a novel strategy of Yersinia pseudotuberculosis in which this pathogen uses a secreted T3SS translocator protein (YopD) to control global RNA regulators. Secretion of the YopD translocator upon host cell contact increases the ratio of post-transcriptional regulator CsrA to its antagonistic small RNAs CsrB and CsrC and reduces the degradosome components PNPase and RNase E levels. This substantially elevates the amount of the common transcriptional activator (LcrF) of T3SS/Yop effector genes and triggers the synthesis of associated virulence-relevant traits. The observed hijacking of global riboregulators allows the pathogen to coordinate virulence factor expression and also readjusts its physiological response upon host cell contact.
Protein secretion plays a pivotal role in the interaction between pathogenic bacteria and their hosts. Pathogenic bacteria utilize different highly sophisticated secretion systems (Type I-VII) to translocate proteins across membranes into eukaryotic target cells in order to manipulate host cell functions and disrupt host homeostasis and immune defenses [1–3]. Of these, the type III secretion system (T3SS) is a key virulence factor in many plant, animal and human pathogenic bacteria that contributes to bacterial survival and colonization [1, 4]. T3SSs are contact-dependent secretion systems. An intimate contact between the pathogen and the eukaryotic target cell is the signal for the bacterium to induce expression of the secretion machinery and its secreted substrates, the so-called effector proteins, as well as the secretion procedure itself. T3SS gene expression and secretion is activated by growth conditions, certain chemicals, and environmental signals (temperature, pH, oxygen availability, host-associated signals) that mimic host cell contact, and by complex feedback control mechanisms [1, 2, 4]. One of the best-studied systems is the Yersinia T3SS [5, 6].
Triggering of T3SS/effector gene expression upon host cell contact is a well-known hallmark of T3SS regulation in many important Gram-negative plant, animal and human pathogens; however, the molecular mechanism initiating this process is still unclear. Up to this point, a role of the translocon protein YopD in this process in Yersinia was assumed [17, 20], but how cell contact is transmitted and translated to trigger this response remained unclear. The translocon protein could have a passive role, e.g. by inducing conformational changes in components of the secretion needle upon translocon formation which then initiates a set of signaling pathways to modulate T3SS/Yop synthesis. Alternatively, YopD could actively control T3SS/yop gene expression. Our data demonstrate that YopD influences synthesis of the T3SS/Yop machinery and that this involves hijacking of multiple RNA regulators, the carbon storage regulator system and the degradosome components RNase E and PNPase.