8sza

Structural highlights

Function

NINJ1_HUMAN Effector of necroptotic and pyroptotic programmed cell death that mediates plasma membrane rupture (cytolysis) (PubMed:33472215, PubMed:36468682, PubMed:37196676, PubMed:37198476). Acts downstream of Gasdermin (GSDMA, GSDMB, GSDMC, GSDMD, or GSDME) or MLKL during pyroptosis or necroptosis, respectively: oligomerizes in response to death stimuli and promotes plasma membrane rupture by introducing hydrophilic faces of 2 alpha helices into the hydrophobic membrane, leading to release intracellular molecules named damage-associated molecular patterns (DAMPs) that propagate the inflammatory response (PubMed:33472215, PubMed:36468682, PubMed:37196676, PubMed:37198476). Acts as a regulator of Toll-like receptor 4 (TLR4) signaling triggered by lipopolysaccharide (LPS) during systemic inflammation; directly binds LPS (PubMed:26677008). Involved in leukocyte migration during inflammation by promoting transendothelial migration of macrophages via homotypic binding (By similarity). Promotes the migration of monocytes across the brain endothelium to central nervous system inflammatory lesions (PubMed:22162058). Also acts as a homophilic transmembrane adhesion molecule involved in various processes such as axonal growth, cell chemotaxis and angiogenesis (PubMed:33028854, PubMed:8780658, PubMed:9261151). Promotes cell adhesion by mediating homophilic interactions via its extracellular N-terminal adhesion motif (N-NAM) (PubMed:33028854). Involved in the progression of the inflammatory stress by promoting cell-to-cell interactions between immune cells and endothelial cells (PubMed:22162058, PubMed:26677008, PubMed:32147432). Plays a role in nerve regeneration by promoting maturation of Schwann cells (PubMed:8780658, PubMed:9261151). Acts as a regulator of angiogenesis (PubMed:33028854). Promotes the formation of new vessels by mediating the interaction between capillary pericyte cells and endothelial cells (By similarity). Promotes osteoclasts development by enhancing the survival of prefusion osteoclasts (By similarity). Also involved in striated muscle growth and differentiation (By similarity).[UniProtKB:O70131]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]} Secreted form generated by cleavage, which has chemotactic activity (By similarity). Acts as an anti-inflammatory mediator by promoting monocyte recruitment, thereby ameliorating atherosclerosis (PubMed:32883094).[UniProtKB:O70131]^[11]

References

1. ↑ Ifergan I, Kebir H, Terouz S, Alvarez JI, Lécuyer MA, Gendron S, Bourbonnière L, Dunay IR, Bouthillier A, Moumdjian R, Fontana A, Haqqani A, Klopstein A, Prinz M, López-Vales R, Birchler T, Prat A. Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions. Ann Neurol. 2011 Nov;70(5):751-63. PMID:22162058 doi:10.1002/ana.22519
2. ↑ Shin MW, Bae SJ, Wee HJ, Lee HJ, Ahn BJ, Le H, Lee EJ, Kim RH, Lee HS, Seo JH, Park JH, Kim KW. Ninjurin1 regulates lipopolysaccharide-induced inflammation through direct binding. Int J Oncol. 2016 Feb;48(2):821-8. PMID:26677008 doi:10.3892/ijo.2015.3296
3. ↑ Toma L, Sanda GM, Raileanu M, Stancu CS, Niculescu LS, Sima AV. Ninjurin-1 upregulated by TNFα receptor 1 stimulates monocyte adhesion to human TNFα-activated endothelial cells; benefic effects of amlodipine. Life Sci. 2020 May 15;249:117518. PMID:32147432 doi:10.1016/j.lfs.2020.117518
4. ↑ Kim SW, Lee HK, Seol SI, Davaanyam D, Lee H, Lee JK. Ninjurin 1 dodecamer peptide containing the N-terminal adhesion motif (N-NAM) exerts proangiogenic effects in HUVECs and in the postischemic brain. Sci Rep. 2020 Oct 7;10(1):16656. PMID:33028854 doi:10.1038/s41598-020-73340-5
5. ↑ Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O'Rourke K, Li Q, Sandoval W, Yan D, Kang J, Xu M, Zhang J, Lee WP, McKenzie BS, Ulas G, Payandeh J, Roose-Girma M, Modrusan Z, Reja R, Sagolla M, Webster JD, Cho V, Andrews TD, Morris LX, Miosge LA, Goodnow CC, Bertram EM, Dixit VM. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021 Mar;591(7848):131-136. PMID:33472215 doi:10.1038/s41586-021-03218-7
6. ↑ Borges JP, Sætra RSR, Volchuk A, Bugge M, Devant P, Sporsheim B, Kilburn BR, Evavold CL, Kagan JC, Goldenberg NM, Flo TH, Steinberg BE. Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death. Elife. 2022 Dec 5;11:e78609. PMID:36468682 doi:10.7554/eLife.78609
7. ↑ Kayagaki N, Stowe IB, Alegre K, Deshpande I, Wu S, Lin Z, Kornfeld OS, Lee BL, Zhang J, Liu J, Suto E, Lee WP, Schneider K, Lin W, Seshasayee D, Bhangale T, Chalouni C, Johnson MC, Joshi P, Mossemann J, Zhao S, Ali D, Goldenberg NM, Sayed BA, Steinberg BE, Newton K, Webster JD, Kelly RL, Dixit VM. Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury. Nature. 2023 Jun;618(7967):1072-1077. PMID:37196676 doi:10.1038/s41586-023-06191-5
8. ↑ Degen M, Santos JC, Pluhackova K, Cebrero G, Ramos S, Jankevicius G, Hartenian E, Guillerm U, Mari SA, Kohl B, Müller DJ, Schanda P, Maier T, Perez C, Sieben C, Broz P, Hiller S. Structural basis of NINJ1-mediated plasma membrane rupture in cell death. Nature. 2023 Jun;618(7967):1065-1071. PMID:37198476 doi:10.1038/s41586-023-05991-z
9. ↑ Araki T, Milbrandt J. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth. Neuron. 1996 Aug;17(2):353-61. PMID:8780658 doi:10.1016/s0896-6273(00)80166-x
10. ↑ Araki T, Zimonjic DB, Popescu NC, Milbrandt J. Mechanism of homophilic binding mediated by ninjurin, a novel widely expressed adhesion molecule. J Biol Chem. 1997 Aug 22;272(34):21373-80. PMID:9261151 doi:10.1074/jbc.272.34.21373
11. ↑ Jeon S, Kim TK, Jeong SJ, Jung IH, Kim N, Lee MN, Sonn SK, Seo S, Jin J, Kweon HY, Kim S, Shim D, Park YM, Lee SH, Kim KW, Cybulsky MI, Shim H, Roh TY, Park WY, Lee HO, Choi JH, Park SH, Oh GT. Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis. Circulation. 2020 Nov 3;142(18):1736-1751. PMID:32883094 doi:10.1161/CIRCULATIONAHA.120.046907