NINJ1

Ninjurin-1 is a protein encoded by the NINJ1 gene in humans.^[5][6] This transmembrane protein plays a critical role in plasma membrane rupture during lytic cell death.^[7] NINJ1 is involved in the terminal stages of cell rupture across various cell death pathways, including pyroptosis, necroptosis, and ferroptosis.^[8] By disrupting cell membranes, NINJ1 facilitates the release of intracellular proteins, such as lactate dehydrogenase and various Damage Associated Molecular Patterns (DAMPs) into the extracellular environment, triggering inflammation.^[7] Upon activation, NINJ1 assembles into a chain-like oligomer that forms a ring structure—dubbed the "Ninja Cutter"—which, like a cookie cutter, cuts and releases membrane disks, enabling cell rupture.^[9]

NINJ1
Identifiers
Aliases	NINJ1, NIN1, NINJURIN, ninjurin 1
External IDs	OMIM: 602062; MGI: 1196617; HomoloGene: 88815; GeneCards: NINJ1; OMA:NINJ1 - orthologs
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9q22.31 Start 93,121,496 bp[1] End 93,134,251 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13|13 A5 Start 49,340,961 bp[2] End 49,349,720 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right adrenal cortex left adrenal gland left adrenal cortex monocyte thoracic aorta ascending aorta Descending thoracic aorta right lobe of liver blood gastric mucosa Top expressed in stroma of bone marrow pyloric antrum right kidney left lobe of liver facial motor nucleus calvaria utricle tibiofemoral joint vestibular sensory epithelium primary oocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding Cellular component integral component of membrane membrane Biological process hyaloid vascular plexus regression cell adhesion nervous system development tissue regeneration positive regulation of cell-matrix adhesion pyroptosis cell death Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4814 18081 Ensembl ENSG00000131669 ENSMUSG00000037966 UniProt Q92982 O70131 RefSeq (mRNA) NM_004148 NM_013610 RefSeq (protein) NP_004139 NP_038638 Location (UCSC) Chr 9: 93.12 – 93.13 Mb Chr 13: 49.34 – 49.35 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Gene

NINJ1 is located on the long arm of chromosome 9 (9q22.31).^[6]

Clinical Significance

Since NINJ1 is involved in inflammatory cell death and release of DAMPs that are important for immune response to infection, loss or inhibition of NINJ1 may promote susceptibility to bacterial infections. This is supported by studies using Ninj1^-/- knockout mice, which are more susceptible to infection with C. rodentium compared to wild type mice.^[8]

NINJ1 circulating plasma levels are elevated in patients with sepsis and correlate with disease severity and mortality, making NINJ1 a potential prognostic biomarker for sepsis monitoring. ^[10]

References

1. GRCh38: Ensembl release 89: ENSG00000131669 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037966 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Araki T, Milbrandt J (Oct 1996). "Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth". Neuron. 17 (2): 353–61. doi:10.1016/S0896-6273(00)80166-X. PMID 8780658. S2CID 12471778.
6. "Entrez Gene: NINJ1 ninjurin 1".
7. Shen, Jinze; Chen, Ruixiu; Duan, Shiwei (2024-11-15). "NINJ1: Bridging lytic cell death and inflammation therapy". Cell Death & Disease. 15 (11): 831. doi:10.1038/s41419-024-07203-6. ISSN 2041-4889. PMC 11564778. PMID 39543132.
8. Kayagaki, Nobuhiko; Kornfeld, Opher S.; Lee, Bettina L.; Stowe, Irma B.; O’Rourke, Karen; Li, Qingling; Sandoval, Wendy; Yan, Donghong; Kang, Jing; Xu, Min; Zhang, Juan; Lee, Wyne P.; McKenzie, Brent S.; Ulas, Gözde; Payandeh, Jian (2021). "NINJ1 mediates plasma membrane rupture during lytic cell death". Nature. 591 (7848): 131–136. Bibcode:2021Natur.591..131K. doi:10.1038/s41586-021-03218-7. ISSN 1476-4687. PMID 33472215.
9. David, Liron; Borges, Jazlyn P.; Hollingsworth, L. Robert; Volchuk, Allen; Jansen, Isabelle; Garlick, Evelyn; Steinberg, Benjamin E.; Wu, Hao (2024). "NINJ1 mediates plasma membrane rupture by cutting and releasing membrane disks". Cell. 187 (9): 2224–2235.e16. doi:10.1016/j.cell.2024.03.008. PMC 11055670. PMID 38614101.
10. Wu, Yongbin; Li, Tao; Tan, Sichuang; Song, Ruoyu; Song, Kaiyuan; Zhou, Jiankang; Xiao, Xianzhong; Wang, Kangkai; Zhang, Huali; Tan, Sipin (2024-08-28). "NINJ1: A Novel Sepsis Severity and Mortality Biomarker". Shock. doi:10.1097/SHK.0000000000002460. ISSN 1073-2322. PMID 39193891.

Further reading

• Guimarães PE, Fridman C, Gregório SP, et al. (2007). "WITHDRAWN: Association between polymorphisms in genes of inflammatory response and axonal repair with spinal cord injury". Spinal Cord. doi:10.1038/sj.sc.3102122. PMID 17893696.
• Cardoso CC, Martinez AN, Guimarães PE, et al. (2007). "Ninjurin 1 asp110ala single nucleotide polymorphism is associated with protection in leprosy nerve damage". J. Neuroimmunol. 190 (1–2): 131–8. doi:10.1016/j.jneuroim.2007.07.015. PMID 17825431. S2CID 20637695.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Toyama T, Sasaki Y, Horimoto M, et al. (2005). "Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells". J. Hepatol. 41 (4): 637–43. doi:10.1016/j.jhep.2004.06.027. PMID 15464245.
• Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9". Nature. 429 (6990): 369–74. Bibcode:2004Natur.429..369H. doi:10.1038/nature02465. PMC 2734081. PMID 15164053.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Chadwick BP, Heath SK, Williamson J, et al. (1998). "The human homologue of the ninjurin gene maps to the candidate region of hereditary sensory neuropathy type I (HSNI)". Genomics. 47 (1): 58–63. doi:10.1006/geno.1997.5084. PMID 9465296.
• Araki T, Zimonjic DB, Popescu NC, Milbrandt J (1997). "Mechanism of homophilic binding mediated by ninjurin, a novel widely expressed adhesion molecule". J. Biol. Chem. 272 (34): 21373–80. doi:10.1074/jbc.272.34.21373. PMID 9261151.

• Degen, Morris; Santos, José Carlos; Pluhackova, Kristyna; Cebrero, Gonzalo; Ramos, Saray; Jankevicius, Gytis; Hartenian, Ella; Guillerm, Undina; Mari, Stefania A.; Kohl, Bastian; Müller, Daniel J.; Schanda, Paul; Maier, Timm; Perez, Camilo; Sieben, Christian (2023-06-29). "Structural basis of NINJ1-mediated plasma membrane rupture in cell death". Nature. 618 (7967): 1065–1071. Bibcode:2023Natur.618.1065D. doi:10.1038/s41586-023-05991-z. ISSN 0028-0836. PMC 10307626. PMID 37198476.
• Pourmal, Sergei; Truong, Melissa E.; Johnson, Matthew C.; Yang, Ying; Zhou, Lijuan; Alegre, Kamela; Stowe, Irma B.; Gupta, Shalini; Chen, Phoebe A.; Zhang, Yingnan; Rohou, Alexis; Newton, Kim; Kayagaki, Nobuhiko; Dixit, Vishva M.; Deshpande, Ishan (2024-10-30). "Autoinhibition of dimeric NINJ1 prevents plasma membrane rupture". Nature: 1–3. doi:10.1038/s41586-024-08273-4. ISSN 1476-4687. PMC 11711097. PMID 39476863.