iNOS Signaling


Pathway Description

Microorganisms have developed several mechanisms to survive in host environments. Such mechanisms include competition with their host for metal acquisition and resistance to host defenses such as nitric oxide (NO), a cytotoxic weapon generated by macrophages. In eukaryotic cells, NO is metabolically produced by nitric oxide synthase (NOS) from L-Arginine. In macrophages, iNOS (NOS2) is produced after activation by endotoxins or cytokines, and generates copious amounts of NO presumably to help kill or inhibit the growth of invading microorganisms. The catalytic activity of iNOS is regulated by the availability of the substrate L-Arginine and CALM, which binds to iNOS. iNOS catalyzes the conversion of L-Arginine into NO and L-Citrulline. NO is a free radical effector of the innate immune system that can directly inhibit pathogen replication. A variety of extracellular stimuli can activate distinct signaling pathways that converge to initiate expression of iNOS. Cell wall components of bacteria and fungi trigger the innate immune signaling cascade, leading to expression of iNOS. Lipopolysaccharide (LPS), a component of the wall of gram-negative bacteria, binds to LBP, which delivers LPS to the high-affinity LPS receptor CD14. TLR4, in conjunction with the small extracellular protein MD2, interacts with the CD14-LPS complex and activates an intracellular signaling cascade via adaptors that include IRAK and MyD88, which leads to activation of NF-κB and p38 MAPK signaling pathways. NF-κB in the nucleus binds to NF-κB elements in the iNOS 5' flanking region, triggering iNOS transcription. Cytokines released from infected host cells also activate NO production. IFNγ activates JAK family kinases to trigger JAK/STAT signaling, leading to synthesis of the transcription factor IRF1 and stimulation of iNOS mRNA transcription.

NO is an antibacterial effector and can inhibit bacterial DNA synthesis by inhibiting bacterial ribonucleotide reductase1/2 and causing double-strand DNA breaks in bacterial DNA. The bacterial protein SoxRS serves as a sensor for, and is activated by NO. It can activate transcription of a set of bacterial genes whose products defend the pathogen from oxidant damage by bacterial SOD. OxyR, a transcription factor involved in stimulation of peroxide detoxification genes, is also activated by NO. It also directs the transcription of bacterial genes such as AHP which protect bacteria against NO. The bacterial protein FUR also serves as an NO sensor. NO inactivates FUR by interacting with its iron cofactor, permitting expression of genes protective against oxidative stress. NO is also an antiviral effector of the innate immune system. It can inhibit replication of herpes viruses, picornaviruses, flaviviruses and corona viruses by targeting viral proteases.