Chinese scientists published an article "Science" revealing the successful protein mechanism of tuberculosis pathogens

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis and remains a major infectious disease threat
to global public health.
It is estimated to have infected 2-3 billion people each year, causing about 1.
5 million deaths
.

Now, a team of Chinese scientists has described a previously undefined pathway
for Mycobacterium tuberculosis to fight host immunity.
Specifically, the researchers identified the known Mtb protein tyrosine phosphatase PtpB as a phospholipid phosphatase that inhibits the host inflamator-pyrotic pathway
by hijacking host ubiquitin.

The study was completed by the team of Professor LIU Cuihua of the Institute of Microbiology of the Chinese Academy of Sciences in collaboration with Professor QIU Xiaobo of Beijing Normal University and published in the journal Science
.

Dr.
LIU's team has been studying the molecular mechanisms of Mycobacterium-host interactions of tuberculosis, and her previous research has provided potential targets for the development of anti-tuberculosis therapeutics based on the pathogen-host interaction interface
.

Mycobacterium tuberculosis is an intracellular pathogen with a variety of intracellular survival strategies, and the complex and dynamic interaction between Mycobacterium tuberculosis and the host determines the occurrence, development and outcome
of tuberculosis.
An interesting feature of MTBs evolved is a group of eukaryotic effectors, but their host targets and regulatory role in pathogen-host interactions remain largely unexplored
.

In this study, LIU's team examined the entire genome of Mycobacterium tuberculosis to predict secreted eukaryotic-like proteins with eukaryotic-like motifs or domains that may directly target host factors
.
These Mtb effector proteins are subsequently subjected to further experimental analysis by the inflammasome remodeling system to screen for inhibitors
of the inflammasome-pyrotic pathway.

Among 201 predicted eukaryotic proteins secreted by Mtb, the scientists found that PtpB is a key bacterial effector that is secreted in large quantities by Mtb to inhibit missing proteins
in the NOD-like receptor protein 3 (NLRP3) and melanoma 2 (AIM2) inflammasome pathways.

Follow-up experiments have shown that PtpB can inhibit GSDMD-dependent cytokine release and cell pyrosis, and promote the survival
of Mtb in macrophages.
Mechanistically, PtpB secreted by Mtb targets and dephosphorylates the host plasma membrane phosphatidylinositol-4-monophosphate (PI4P) and phosphatidinositol-(4,5)-bisphosphate [PI(4,5)P2] to inhibit membrane localization of GSDMD-N-terminal cleavage fragments (GSDMD-N), thereby preventing GSDMD-mediated immune responses
.

Interestingly, this phosphatase activity requires PtpB to bind
to ubiquitin through its unique ubiquitin interaction motif (UIM)-like region.
Disruption of phospholipid phosphatase activity, or the UIM-like region of PtpB, enhances the host GSDMD-dependent immune response, thereby reducing intracellular pathogen survival
.

This study reveals a previously unrecognized strategy for pathogens to inhibit pyrogenesis and counter host immunity
by altering host membrane composition.
The results could lead to the development of
a potential tuberculosis treatment targeting the PtpB-Ub-phospholipid-pyroptosis axis.

A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin