Yasu Morita

Overview

The genus Mycobacterium includes a number of pathogenic species that cause various diseases such as tuberculosis and leprosy. The research goal of our laboratory is to understand the pathogenesis of these medically important bacteria, especially focusing on the biogenesis and functions of the plasma membrane (PM) and cell wall (CW). In fact, the multi-layered, highly impermeable complex of PM/CW represents a major virulence determinant of pathogenic mycobacteria. While PM/CW biogenesis is a proven drug target, the synthesis and functions of PM/CW components and the assembly of the PM/CW complex remain poorly defined at the molecular level. Our research is aimed at clarifying several key aspects of PM/CW biogenesis and functions using glycobiological, biochemical, and cell biological approaches.

Glycolipid biosynthesis as a potential drug target

The mannose-modified lipids, phosphatidylinositol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM) together represent an important class of glycolipids present in the mycobacterial PM/CW. PIMs are glycoslyated phosphatidylinositols (PIs) with their inositol moiety modified by either two (AcPIM2) or six mannoses (AcPIM6)(Fig. 1). LM carries a much longer chain of mannoses attached to a PI. LAM is an arabinosylated LM, in which ~70 residues of arabinofuranose form arabinan moieties. In pathogenic mycobacteria, these glycolipids are considered as important immunomodulatory molecules that modulate the profiles of cytokine productions, prevent apoptosis, and block phagosome maturation. We are interested in clarifying the biosynthesis of these glycolipids and examining if the biosynthesis of these glycolipids
can be a potential drug target.

Functional compartmentalization of mycobacterial plasma membrane

Bacterial PM has been considered as a homogenous fluid matrix based primarily on the traditional fluid mosaic model. This stereotypical view cannot explain how numerous membrane-associated biological processes are organized and coordinated in bacteria. In fact, our study suggests that more intricate organization of plasma membrane could be important for the metabolic regulation of glycolipid biosynthesis in mycobacteria (Morita, 2005). Our goal is to elucidate the function of plasma membrane compartmentalization in mycobacteria, reveal the molecular mechanisms that govern the dynamics, and examine its importance in mycobacterial pathogenesis.

Bacterial PI3P Signalling

We recently discovered that phosphatidylinositol 3-phosphate (PI3P) exists in mycobacteria (Morita, 2010). We further showed that PI3P synthesis is elevated in response to changes in salinity, suggesting a potential role as a second messenger. PI3P or any other polyphosphoinositides have never been identified in bacteria, and it remains unclear how PI3P is biosynthesized and if it acts as a signalling molecule. In this line of research, we aim to reveal the metabolic pathways and functional roles of PI3P at the molecular level.