The Pup-Proteasome System of Mycobacterium tuberculosis
Proteasomes are ATP-dependent protein degradation machines present in all archaea and eukaryotes, and found in several bacterial species of the order Actinomycetales. Mycobacterium tuberculosis (Mtb), an Actinomycete pathogenic to humans, requires proteas
- PDF / 842,922 Bytes
- 29 Pages / 439.37 x 666.14 pts Page_size
- 21 Downloads / 191 Views
The Pup-Proteasome System of Mycobacterium tuberculosis Marie I. Samanovic, Huilin Li, and K. Heran Darwin
Abstract Proteasomes are ATP-dependent protein degradation machines present in all archaea and eukaryotes, and found in several bacterial species of the order Actinomycetales. Mycobacterium tuberculosis (Mtb), an Actinomycete pathogenic to humans, requires proteasome function to cause disease. In this chapter, we describe what is currently understood about the biochemistry of the Mtb proteasome and its role in virulence. The characterization of the Mtb proteasome has led to the discovery that proteins can be targeted for degradation by a small protein modifier in bacteria as they are in eukaryotes. Furthermore, the understanding of proteasome function in Mtb has helped reveal new insight into how the host battles infections.
Introduction Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and kills nearly two million people every year (http://www.who.int/). The infectious process starts with the inhalation of air-borne droplets containing Mtb bacilli. Bacteria replicate in professional phagocytes in the lungs where they must combat numerous anti-microbial molecules. If the host cannot control the infection, Mtb growth will result in the destruction of lung tissues and, ultimately, the death of the host.
M.I. Samanovic • K.H. Darwin (*) Department of Microbiology, New York University School of Medicine, 550 First Avenue, MSB 236, New York, NY 10016, USA e-mail: [email protected] H. Li Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA Brookhaven National Laboratory Biology Department, Brookhaven National Laboratory, 50 Bell Ave, Upton, Brookhaven, NY 11973-5000, USA D.A. Dougan (ed.), Regulated Proteolysis in Microorganisms, Subcellular Biochemistry 66, 267 DOI 10.1007/978-94-007-5940-4_10, © Springer Science+Business Media Dordrecht 2013
268
M.I. Samanovic et al.
Despite the astounding mortality caused by TB, most individuals infected with Mtb can control mycobacterial growth for much of their lives. Among the host’s arsenal of antimicrobial effectors is nitric oxide (NO), which is produced by activated macrophages and is toxic to numerous microbes [1]. Evidence that supports the notion that NO is critical to controlling Mtb has come from mouse studies. Inactivation of the macrophage associated inducible NO synthase, (iNOS) also known as NOS2, dramatically sensitizes mice to Mtb infections [2]. The cytotoxic effects of NO are likely to be dependent on the formation of highly reactive nitrogen intermediates (RNIs). It is thought that in host cells NO is oxidized to nitrite, which can be protonated to nitrous acid in the phagosomes of activated macrophages. Nitrous acid dismutates to reform NO, which can penetrate bacterial membranes and cell walls to combine with reactive oxygen intermediates (ROIs) such as superoxide to generate peroxynitrite. RNIs and ROIs can induce lethal injuries including DNA and protein damage as well as
Data Loading...
