9bia

Structural highlights

Function

NINJ1_MOUSE Effector of various programmed cell death, such as pyroptosis and necroptosis, which mediates plasma membrane rupture (cytolysis) (PubMed:19557008, PubMed:33472215, PubMed:36468682, PubMed:37196676, PubMed:37198476). Oligomerizes in response to death stimuli and forms ring-like structures on the plasma membrane: acts by cutting and shedding membrane disks, like a cookie cutter, leading to membrane damage and loss that cannot be repaired by the cell (PubMed:33472215, PubMed:37196676, PubMed:37198476). Plasma membrane rupture leads to release intracellular molecules named damage-associated molecular patterns (DAMPs) that propagate the inflammatory response (PubMed:33472215, PubMed:37196676, PubMed:37198476). Mechanistically, mediates plasma membrane rupture by introducing hydrophilic faces of 2 alpha helices into the hydrophobic membrane (PubMed:37198476). Induces plasma membrane rupture downstream of Gasdermin (GSDMA, GSDMB, GSDMC, GSDMD, or GSDME) or MLKL during pyroptosis or necroptosis, respectively (PubMed:33472215, PubMed:37196676, PubMed:37198476). Acts as an effector of PANoptosis downstream of CASP1, CASP4, CASP8 and RIPK3 (PubMed:38409108). Also induces plasma membrane rupture in response to cell swelling caused by osmotic stress and ferroptosis downstream of lipid peroxidation (PubMed:37980412, PubMed:38396301). Acts as a regulator of Toll-like receptor 4 (TLR4) signaling triggered by lipopolysaccharide (LPS) during systemic inflammation; directly binds LPS (PubMed:25860173). Involved in leukocyte migration during inflammation by promoting transendothelial migration of macrophages via homotypic binding (PubMed:24917672). Promotes the migration of monocytes across the brain endothelium to central nervous system inflammatory lesions (By similarity). Also acts as a homophilic transmembrane adhesion molecule involved in various processes such as axonal growth, cell chemotaxis and angiogenesis (PubMed:24347169, PubMed:24917672, PubMed:31526566). Promotes cell adhesion by mediating homophilic interactions via its extracellular N-terminal adhesion motif (N-NAM) (PubMed:24917672, PubMed:30510259). Involved in the progression of the inflammatory stress by promoting cell-to-cell interactions between immune cells and endothelial cells (PubMed:24917672, PubMed:30510259). Plays a role in nerve regeneration by promoting maturation of Schwann cells (PubMed:31526566). Acts as a regulator of angiogenesis (PubMed:25766274, PubMed:30354207). Promotes the formation of new vessels by mediating the interaction between capillary pericyte cells and endothelial cells (PubMed:25766274, PubMed:30354207). Also mediates vascular functions in penile tissue as well as vascular formation (PubMed:24979788). Promotes osteoclasts development by enhancing the survival of prefusion osteoclasts (PubMed:30700695). Also involved in striated muscle growth and differentiation (PubMed:31091274). Also involved in cell senescence in a p53/TP53 manner, possibly by acting as an indirect regulator of p53/TP53 mRNA translation (PubMed:23690620, PubMed:29073078).[UniProtKB:Q92982]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]} Secreted form generated by cleavage, which has chemotactic activity (PubMed:23142597). Acts as an anti-inflammatory mediator by promoting monocyte recruitment, thereby ameliorating atherosclerosis (PubMed:32883094).^{[21] [22]}

References

1. ↑ Lee HJ, Ahn BJ, Shin MW, Jeong JW, Kim JH, Kim KW. Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development. Cell Death Differ. 2009 Oct;16(10):1395-407. PMID:19557008 doi:10.1038/cdd.2009.78
2. ↑ Cho SJ, Rossi A, Jung YS, Yan W, Liu G, Zhang J, Zhang M, Chen X. Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9362-7. PMID:23690620 doi:10.1073/pnas.1221242110
3. ↑ Ahn BJ, Le H, Shin MW, Bae SJ, Lee EJ, Wee HJ, Cha JH, Lee HJ, Lee HS, Kim JH, Kim CY, Seo JH, Lo EH, Jeon S, Lee MN, Oh GT, Yin GN, Ryu JK, Suh JK, Kim KW. Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice. J Biol Chem. 2014 Feb 7;289(6):3328-38. PMID:24347169 doi:10.1074/jbc.M113.498212
4. ↑ Ahn BJ, Le H, Shin MW, Bae SJ, Lee EJ, Lee SY, Yang JH, Wee HJ, Cha JH, Seo JH, Lee HS, Lee HJ, Arai K, Lo EH, Jeon S, Oh GT, Kim WJ, Ryu JK, Suh JK, Kim KW. Ninjurin1 enhances the basal motility and transendothelial migration of immune cells by inducing protrusive membrane dynamics. J Biol Chem. 2014 Aug 8;289(32):21926-36. PMID:24917672 doi:10.1074/jbc.M113.532358
5. ↑ Yin GN, Choi MJ, Kim WJ, Kwon MH, Song KM, Park JM, Das ND, Kwon KD, Batbold D, Oh GT, Koh GY, Kim KW, Ryu JK, Suh JK. Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse. Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):E2731-40. PMID:24979788 doi:10.1073/pnas.1403471111
6. ↑ Matsuki M, Kabara M, Saito Y, Shimamura K, Minoshima A, Nishimura M, Aonuma T, Takehara N, Hasebe N, Kawabe J. Ninjurin1 is a novel factor to regulate angiogenesis through the function of pericytes. Circ J. 2015;79(6):1363-71. PMID:25766274 doi:10.1253/circj.CJ-14-1376
7. ↑ Jennewein C, Sowa R, Faber AC, Dildey M, von Knethen A, Meybohm P, Scheller B, Dröse S, Zacharowski K. Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation. Am J Respir Cell Mol Biol. 2015 Nov;53(5):656-63. PMID:25860173 doi:10.1165/rcmb.2014-0354OC
8. ↑ Yang HJ, Zhang J, Yan W, Cho SJ, Lucchesi C, Chen M, Huang EC, Scoumanne A, Zhang W, Chen X. Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11500-11505. PMID:29073078 doi:10.1073/pnas.1711814114
9. ↑ Minoshima A, Kabara M, Matsuki M, Yoshida Y, Kano K, Tomita Y, Hayasaka T, Horiuchi K, Saito Y, Aonuma T, Nishimura M, Maruyama K, Nakagawa N, Sawada J, Takehara N, Hasebe N, Kawabe JI. Pericyte-Specific Ninjurin1 Deletion Attenuates Vessel Maturation and Blood Flow Recovery in Hind Limb Ischemia. Arterioscler Thromb Vasc Biol. 2018 Oct;38(10):2358-2370. PMID:30354207 doi:10.1161/ATVBAHA.118.311375
10. ↑ Choi S, Woo JK, Jang YS, Kang JH, Hwang JI, Seong JK, Yoon YS, Oh SH. Ninjurin1 Plays a Crucial Role in Pulmonary Fibrosis by Promoting Interaction between Macrophages and Alveolar Epithelial Cells. Sci Rep. 2018 Dec 3;8(1):17542. PMID:30510259 doi:10.1038/s41598-018-35997-x
11. ↑ Bae SJ, Shin MW, Son T, Lee HS, Chae JS, Jeon S, Oh GT, Kim KW. Ninjurin1 positively regulates osteoclast development by enhancing the survival of prefusion osteoclasts. Exp Mol Med. 2019 Jan 16;51(1):1-16. PMID:30700695 doi:10.1038/s12276-018-0201-3
12. ↑ Kny M, Csályi KD, Klaeske K, Busch K, Meyer AM, Merks AM, Darm K, Dworatzek E, Fliegner D, Baczko I, Regitz-Zagrosek V, Butter C, Luft FC, Panáková D, Fielitz J. Ninjurin1 regulates striated muscle growth and differentiation. PLoS One. 2019 May 15;14(5):e0216987. PMID:31091274 doi:10.1371/journal.pone.0216987
13. ↑ Tomita Y, Horiuchi K, Kano K, Tatsukawa T, Matsuo R, Hayasaka T, Yoshida Y, Kabara M, Yasuda S, Nakajima K, Nakagawa N, Takehara N, Okizaki A, Hasebe N, Kawabe JI. Ninjurin 1 mediates peripheral nerve regeneration through Schwann cell maturation of NG2-positive cells. Biochem Biophys Res Commun. 2019 Nov 12;519(3):462-468. PMID:31526566 doi:10.1016/j.bbrc.2019.09.007
14. ↑ 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
15. ↑ 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
16. ↑ 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
17. ↑ 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
18. ↑ Dondelinger Y, Priem D, Huyghe J, Delanghe T, Vandenabeele P, Bertrand MJM. NINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis. Cell Death Dis. 2023 Nov 18;14(11):755. PMID:37980412 doi:10.1038/s41419-023-06284-z
19. ↑ Ramos S, Hartenian E, Santos JC, Walch P, Broz P. NINJ1 induces plasma membrane rupture and release of damage-associated molecular pattern molecules during ferroptosis. EMBO J. 2024 Apr;43(7):1164-1186. PMID:38396301 doi:10.1038/s44318-024-00055-y
20. ↑ Han JH, Karki R, Malireddi RKS, Mall R, Sarkar R, Sharma BR, Klein J, Berns H, Pisharath H, Pruett-Miller SM, Bae SJ, Kanneganti TD. NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress. Nat Commun. 2024 Feb 26;15(1):1739. PMID:38409108 doi:10.1038/s41467-024-45466-x
21. ↑ Ahn BJ, Le H, Shin MW, Bae SJ, Lee EJ, Wee HJ, Cha JH, Park JH, Lee HS, Lee HJ, Jung H, Park ZY, Park SH, Han BW, Seo JH, Lo EH, Kim KW. The N-terminal ectodomain of Ninjurin1 liberated by MMP9 has chemotactic activity. Biochem Biophys Res Commun. 2012 Nov 30;428(4):438-44. PMID:23142597 doi:10.1016/j.bbrc.2012.10.099
22. ↑ 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