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Deciphering the Molecular Mechanism and Function of Pore-Forming Toxins Using Leishmania major
Published on: October 28, 2022
The major surface protease (MSP or GP63) of Leishmania sp. Biosynthesis, regulation of expression, and function
Chaoqun Yao1, John E Donelson, Mary E Wilson
1VA Medical Center, University of Iowa, Iowa City, IA 52242, USA. chaoqun-yao@uiowa.edu
Abstract:
Leishmania sp. are digenetic protozoa that cause an estimated 1.5-2 million new cases of leishmaniasis per year worldwide. Among the molecular factors that contribute to Leishmania sp. virulence and pathogenesis is the major surface protease, alternately called MSP, GP63, leishmanolysin, EC3.4.24.36, and PSP, which is the most abundant surface protein of leishmania promastigotes. Recent studies using gene knockout, antisense RNA and overexpression mutants have demonstrated a role for MSP in resistance of promastigotes to complement-mediated lysis and either a direct or indirect role in receptor-mediated uptake of leishmania. The MSP gene clusters in different Leishmania sp. include multiple distinct MSPs that tend to fall into three classes, which can be distinguished by their sequences and by their differential expression in parasite life stages. Regulated expression of MSP class gene products during the parasite life cycle occurs at several levels involving both mRNA and protein metabolism. In this review we summarize advances in MSP research over the past decade, including organization of the gene families, crystal structure of the protein, regulation of mRNA and protein expression, biosynthesis and possible functions. The MSPs exquisitely demonstrate the multiple levels of post-transcriptional gene regulation that occur in Leishmania sp. and other trypanosomatid protozoa.
Insights
The major surface protease (MSP) is crucial for Leishmania virulence, aiding parasite survival against host defenses and promoting cellular entry. Its complex gene families and post-transcriptional regulation highlight its importance in parasite pathogenesis.
Area of Science:
- Parasitology
- Molecular Biology
- Biochemistry
Background:
- Leishmania parasites cause leishmaniasis, a disease with millions of annual cases globally.
- The major surface protease (MSP), also known as GP63 or leishmanolysin, is the most abundant surface protein on Leishmania promastigotes.
- MSP plays a significant role in parasite virulence, contributing to resistance against host immune mechanisms and cellular uptake.
Purpose of the Study:
- To review recent advances in understanding the major surface protease (MSP) of Leishmania parasites.
- To summarize the organization of MSP gene families, protein structure, expression regulation, biosynthesis, and functions.
- To highlight the role of MSP in Leishmania pathogenesis and host-parasite interactions.
Main Methods:
- Review of gene knockout, antisense RNA, and overexpression studies.
- Analysis of MSP gene cluster organization and sequence diversity.
- Examination of post-transcriptional gene regulation mechanisms at mRNA and protein levels.
Main Results:
- MSP is essential for Leishmania promastigote resistance to complement-mediated lysis.
- MSP is implicated in receptor-mediated uptake of Leishmania by host cells.
- Leishmania species possess multiple MSPs, categorized into three main classes with differential expression.
- Complex post-transcriptional regulation governs MSP expression throughout the parasite life cycle.
Conclusions:
- The major surface protease (MSP) is a key virulence factor in Leishmania, essential for parasite survival and infection.
- MSP exhibits intricate regulation at multiple post-transcriptional levels, characteristic of trypanosomatid protozoa.
- Further research into MSP functions and regulation can inform therapeutic strategies against leishmaniasis.
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