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Pathway of NF-kB Activation
Bacteria
核
細胞質
Pathway of NF-kB Activation
Cytokine such as TNF-, and environmental hazards such as inonizing
radiation, toxic substances trigger the nuclear translocation of NK-kB via
activation of inhibitor-of- NF-kB (IkB) kinase complex (IKK).
IKK phosphorylates IkB bound to NF-kB which consists of a dimer of Rel
family proteins such as p65 and p50. This phosphorylation is the signal for
ubiquitination of IkB by a ubiquitin ligase (UbL). This produces IkB for
degradation by the proteasomes, which then results in the release of NF-kB.
The transcription factor is now free to become translocated to the nucleus
where it binds to specific DNA elements and activates transcription of
NF-kB-dependent genes.
Nitric Oxide (NO)
- a cell mediator regulates numerous physiological processes
• neuro-transmission
• smooth muscle contractility
• platelet reactivity
• cytotoxic activity of immune cells
inappropriate release of NO has been linked to the pathogenesis of a number of disease states !!
 Overproduction of NO by synthase: septic shock, neurodegenerative disorders, and inflammation
Inhibitors of NO synthase
Nitrous oxide (N2O): agent for general anesthesia
Mechanism of Action of NO
Most of the physiological actions are brought by its
activation of the soluble guanylate cyclase; increase
about ~400 fold and formation of cGMP (second
messenger)
Prolonged exposure of NO inhibits the activity of a number
of enzymes; aconitase, cytochrome c oxidase and DNA
synthesis is impaired by the inhibitory action of NO on RNA
reductase; cytotoxic action of NO is produced on invading
micro-organisms.
NO Synthase
An enzyme has four isozymes
• nNOS (or NOS I); regulated by Ca++ and calmodulin, and
found in neural cells and human bronchi epithelium and skeletal
muscle.
• iNOS (or NOS II); Ca++ -independent form and induced by
inflammatory mediator, and exist a variety of cells
• eNOS (or NOS III); Ca++/calmodulin requiring, exists in
vascular endothelial cells and a variety of neuronal cells including
brain
 catalyze the enzymatic reaction with L-arginine (substrate)
and requires various cofactors producing NO.
Fatty Acid
Arachidonic
acid
Cox-1
Cox-2
Prostaglandin
PG: Prostaglandin
Replication cycle of HIV
Replication cycle of HIV
The viral envelope protein (Env) of HIV binds CD4 first, undergoes a conformational
change, then binds one of two chemokine receptors (CCR5 and CXCR4) and enters cells
by fusion of the viral and cellular membranes. Uncoating of the viral capsid releases the
pre-integration complex, which is routed to nuclear pores, along the microtubular networks.
Reversetranscription yields double-stranded viral complementary DNA, which integrates
into host genome. Viral mRNA are transcribed from promoter elements in the 5’ LTR region.
Cellular activation increases the level of transcription, which is augmented greatly by the
viral transcriptional transactivator protein (Tat). Regulator of virion gene expressioin (Rev)
transport singly spliced (ss) and unspliced genomic transcripts from the nucleus to cytoplasm.
Viral structure and enzymatic proteins are synthesized and transported to the plasma
membrane. Late domains in group-specific antigen (Gag) then recruit components of multivesicular bodies to the site of budding so that progeny virions are released from the infected
cells. The four accessory proteins (Nef, Vif, Vpr, and Vpu) and two regulatory proteins
(Rev and Tat) are represented colored circles.
Peterlin, B.M. and D. Trono, 2003. Hide, shield, and strike back; how HIV-infected cells
avoid immune eradication. Nat Rev Immunol. 3:97~107.