Nitric oxide synthase 2 (inducible) explained

Nitric oxide synthase, inducible is an enzyme which is encoded by the NOS2 gene in humans and mice.^[1]

Genetics

Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. Alternative splicing of this gene results in two transcript variants encoding different isoforms.^[2]

Location

Nitric oxide synthase is expressed in epithelial cells of the liver, lung and bone marrow. It is inducible by a combination of lipopolysaccharide and certain cytokines.

Function

Nitric oxide is a reactive free radical mediating in neurotransmission, antimicrobial and antitumoral activities.In mice, the function of Nos2 in immunity against a number of viruses, bacteria, fungi, and parasites has been well characterized, whereas in humans the role of NOS2 has remained elusive and controversial.^[3] Nos2 is important for protective immunity against CMV.

Caveolin 1 has been shown to interact with Nitric oxide synthase 2A.^[4] and Rac2.^[5]

Deficiency

Autosomal recessive NOS2 deficiency has been described in mice. They lack the gene encoding nitric oxide synthase 2 (Nos2) and are susceptible to murine CMV infection.^[6]

In February 2020, the same autosomal recessive, complete NOS2 deficiency was described in a human. A 51-year-old previously healthy person died after 29 months of progressive CMV infection due to respiratory failure secondary to CMV pneumonitis, CMV encephalitis, and hemophagocytic lymphohistiocytosis. Whole-exome sequencing on genomic DNA from his blood showed he had homozygous variants in five genes. The only loss-of-function variant was a homozygous frameshift mutation in nitric oxide synthase 2. This condition is extremely rare, occurring in fewer than 1 per million persons.^[7]

Notes and References

1. Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR . Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes . Proceedings of the National Academy of Sciences of the United States of America . 90 . 8 . 3491–3495 . April 1993 . 7682706 . 46326 . 10.1073/pnas.90.8.3491 . free . 1993PNAS...90.3491G .
2. Web site: Entrez Gene: NOS2A nitric oxide synthase 2A (inducible, hepatocytes).
3. Nathan C . Role of iNOS in human host defense . Science . 312 . 5782 . 1874b–1875b . June 2006 . 16809512 . 10.1126/science.312.5782.1874b . 37395425 .
4. Felley-Bosco E, Bender FC, Courjault-Gautier F, Bron C, Quest AF . Caveolin-1 down-regulates inducible nitric oxide synthase via the proteasome pathway in human colon carcinoma cells . Proceedings of the National Academy of Sciences of the United States of America . 97 . 26 . 14334–14339 . December 2000 . 11114180 . 18919 . 10.1073/pnas.250406797 . free . 2000PNAS...9714334F .
5. Kuncewicz T, Balakrishnan P, Snuggs MB, Kone BC . Specific association of nitric oxide synthase-2 with Rac isoforms in activated murine macrophages . American Journal of Physiology. Renal Physiology . 281 . 2 . F326-F336 . August 2001 . 11457725 . 10.1152/ajprenal.2001.281.2.F326 . 15719851 .
6. Noda S, Tanaka K, Sawamura S, Sasaki M, Matsumoto T, Mikami K, Aiba Y, Hasegawa H, Kawabe N, Koga Y . Role of nitric oxide synthase type 2 in acute infection with murine cytomegalovirus . Journal of Immunology . 166 . 5 . 3533–3541 . March 2001 . 11207313 . 10.4049/jimmunol.166.5.3533 . free .
7. Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, Hum D, Bryk R, Hernandez N, Belkaya S, Rapaport F, Bigio B, Fisch R, Rahman M, Khan T, Al Ali F, Marjani M, Mansouri N, Lorenzo-Diaz L, Emile JF, Marr N, Jouanguy E, Bustamante J, Abel L, Boisson-Dupuis S, Béziat V, Nathan C, Casanova JL . Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency . The New England Journal of Medicine . 382 . 5 . 437–445 . January 2020 . 31995689 . 7063989 . 10.1056/NEJMoa1910640 .