The Proteasome of Mycobacterium tuberculosis Is Required for Resistance to Nitric Oxide

SCIENCE, VOL 302, 1963-1966, 12 DECEMBER, 2003.

Speaker: 張振田                              Time: 1/5/2005, 15:00 – 16:00

Commentator: 余俊強 老師                     Place: Room 601

Abstract:

  Mycobacterium tuberculosis (Mtb) is a very successful pathogen of the human.  It currently infects two billion people worldwide. During the period of latent infection, macrophages are the cells primarily responsible for the resistance against Mtb.  Although iNOS-induced NO and other RNIs within the phagosome of activated macrophages are known to have potent bactriostatic and bactericidal effect, a small number of viable mycobacteria often persists in the cells for a long time and sometimes resume growth and lead to reactivation of the disease.  To identify Mtb genes responsible for resistance to RNIs, the authors screened 10,100 transposon– induced mutants with nitrite at pH5.5, which mimics the internal condition of phagosomes of activated macrophages. Twelve mutants with hypersusceptibility of acidified nitrite were selected.  Five of them had insertions in two genes (Rv2115c and Rv2097c), which are a triple-ATPase homolog involved in protein unfolding in proteasomes and a proteasome accessory factor capable of interacting withα and β subunits of the core particle.  The authors then performed in vitro and in vivo tests to confirm the susceptibility to acidified nitrite in the mutant strains.  In addition, the treatment of proteasomal protease inhibitors (MLN-273 and epoxocimicin) also induced similar phenotypes in wild–typeMtb, while the complementation with an integrative plasmid encoding wild-type Rv2115c restored the resistance to acidified nitrite in the Rv2155c-77 mutant.  Although the structure and function of the bacterial proteasome still remains to be fully investigated, the authors inferred that the Rv2115c and Rv2097c participate in proteasome function at a site analogous to eukaryotic proteasomal regulatory cap structures, which are distinct from the proteasomal protease.  In conclusion, the proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide.

References:

1.      W. Baumeister, J. Walz, F. Zuhl, and E. Seemuller. The Proteasome: Paradigm of a Self-Compartmentalizing Protease. Cell, Vol 92, 367-380, February 6, 1998.

2.      C. Nathan. Inducible Nitric Oxide Synthase in the Tuberculous Human Lung.

Am. J. Respir. Crit. Care Med., Vol 166, 130-131, 2002.