-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Tuberculosis (TB) is a major chronic infectious disease caused by infection with Mycobacterium tuberculosis (Mtb).
。 According to the World Health Organization, there were nearly 9.
9 million new TB patients worldwide in 2020, and about 1.
51 million people had TB Infection leads to death
.
Liu Cuihua's team at the Institute of Microbiology, Chinese Academy of Sciences has long been committed to the research on the mechanism of Mtb interaction between Mtb and host, and in recent years has been working in Nature Immunology (2015).
Nature Communications （2019，2017）、Autophagy（2021）、 EMBO Report （2021）、Cellular & Molecular Immunology（2018，2019 ) and other journals published a series of research works, revealing a series of dynamic processes and molecular mechanisms of the mutual game between pathogenic bacteria and hosts, providing a variety of new ideas and potential new targets for TB prevention and control
.
Recently, Liu Cuihua's team and Qiu Xiaobo's team at Beijing Normal University revealed a new pathogenic immune escape mechanism in which Mtb uses lipphosphatase PtpB to hold host ubiquitin hostage and antagonize GSDMD-mediated cell pyrosis, providing pathogen-based immune evasion -New ideas and potential targets for TB therapy at host interaction interface
.
Inflammasome is a polyprotein complex found in mammalian immune cells in recent years, mainly composed of pattern recognition receptors (such as NLRP3 and AIM2) in the cytoplasm and apoptosis-related spot-like proteins ().
ASC) and pro-caspase-1
.
When stimulated by an activation signal, the inflammasome is able to rapidly assemble and self-cleave pro-caspase-1 to produce an enzymatically active caspase-1, which further cleaves the key effector gasdermin D downstream ( GSDMD) and inflammatory cytokine precursors pro-IL-1β and pro-IL-18, N- of sheared GSDMD The end-effect domain (GSDMD-N) then aggregates and creates pores on the medial side of the plasma membrane, mediating the release of mature inflammatory cytokines (IL-1β and IL-18) and pyrocytosis ().
pyroptosis
).
Studies have suggested that the inflammasome-cell pyrostic pathway plays an important role
in host resistance to infection by pathogens such as Mtb.
However, whether and how these pathogens can escape this immune mechanism is unclear
.
Therefore, further identification of the key effector proteins of pathogens such as Mtb in regulating the host inflammasome-cell pyrostic pathway and elucidating their mechanism of action are expected to provide new drug targets and intervention strategies
for infectious diseases such as TB.
In this study, the researchers identified Mtb-encoded eukaryotic-like secreted proteins by comprehensively screening the recombinant system of AIM2 and NLRP3 inflammasomes constructed in HEK293T cells The protein phosphatase PtpB secreted by Mtb is a potential inhibitory molecule
of the host inflammasome-cell pyrostic pathway.
Further studies have shown that PtpB can be localized to the host cytoplasmic membrane in Mtb infection and rely on its phosphatase activity to dephosphoryl phosphatidylinositol-4-monophosphate (PI4P) on the plasma membrane and phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2), thereby inhibiting the aggregation of GSDMD-N on the plasma membrane and preventing cell pyroscopy and cytokines Release
of IL-1β and IL-18.
Although PtpB has significant functions of dephosphorylating PI4P and PI(4,5)P2 in cells, it only exhibits limited lipophosphatase activity
outside cells.
Structural biological analysis showed that the enzymatic activity center (P-loop) of PtpB was masked within a cap-like flexible double helix structure (lid), suggesting that its phosphatase activity may be dynamically regulated
.
In previous work, Liu's team found that Mtb-encoded another protein phosphatase, PtpA, can exert immunosuppressive function by binding to host ubiquitin to regulate its own phosphatase activity (Nature Immunology ，2015）
。 On this basis, the researchers theorized that the phosphatase activity of PtpB may also be regulated
by specific molecules in the host cell.
Further investigation confirmed that PtpB relies on a special eukaryotic ubiquitin-binding module (UIM-like) to bind to and activate host ubiquitin through hydrophobic interactions to dephosphorylate PI4P and PI ( 4,5)P2, resulting in a significant decrease in the abundance of these two molecules on the plasma membrane of the host cell and inhibiting the aggregation of GSDMD-N on the plasma membrane and the occurrence
of cell pyrosis.
Subsequent mouse infection experiments showed that destroying the lipphosphatase activity or ubiquitin-binding region of PtpB could significantly enhance the host's protective immune response and clearance of Mtb in the early stage of infection, and alleviate the pathological immune damage of the host in the late stage of infection
。
The results have been published online in the internationally authoritative journal Science, entitled "A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin.
" ”
。 Chai Qiyao, special research assistant of Liu Cuihua's research group, Yu Shanshan, a visiting graduate student, and Zhong Yanzhao, a doctoral student, are the joint first authors of the paper, and Liu Cuihua, researcher Wang Jing, researcher of the Institute of Microbiology, Chinese Academy of Sciences, and Professor Qiu Xiaobo of Beijing Normal University are co-corresponding authors
.
This work was supported by the National Natural Science Foundation of China, the National Key Research and Development Program of China, the Strategic Leading Science and Technology Special Project of the Chinese Academy of Sciences (Category B), the Youth Innovation Promotion Association of the Chinese Academy of Sciences, and the China Postdoctoral Science Foundation.
Figure 1 Mycobacterium tuberculosis hijacks ubiquitin to regulate host membrane lipid homeostasis and inhibits cell pyrosis
Article link:
