MAGI-1 Interacts with Nephrin to Maintain Slit Diaphragm Structure through Enhanced Rap1 Activation in Podocytes

被引:19
作者
Ni, Jie [1 ,2 ]
Bao, Sujin [3 ]
Johnson, Ruth I. [4 ]
Zhu, Bingbing [1 ,5 ]
Li, Jianhua [1 ]
Vadaparampil, Justin [1 ]
Smith, Christopher M. [1 ]
Campbell, Kirk N. [1 ]
Grahammer, Florian [6 ]
Huber, Tobias B. [6 ,7 ,8 ,9 ]
He, John C. [1 ]
D'Agati, Vivette D. [10 ]
Chan, Andrew [11 ]
Kaufman, Lewis [1 ]
机构
[1] Icahn Sch Med Mt Sinai, Div Nephrol, New York, NY 10029 USA
[2] Harbin Med Univ, Affiliated Hosp 1, Div Nephrol, Harbin 150001, Peoples R China
[3] Wesleyan Univ, St James Sch Med, St Vincent & Grenadines, Middletown, CT 06459 USA
[4] Wesleyan Univ, Dept Biol, Middletown, CT 06459 USA
[5] Shanghai Univ Tradit Chinese Med, Putuo Hosp, Lab Renal Dis, Dept Nephrol, Shanghai 200062, Peoples R China
[6] Univ Freiburg, Dept Med 4, Med Ctr, Fac Med, D-79106 Freiburg, Germany
[7] Albert Ludwigs Univ Freiburg, BIOSS Ctr Biol Signaling Studies, D-79104 Freiburg, Germany
[8] Albert Ludwigs Univ Freiburg, FRIAS, Freiburg Inst Adv Studies, D-79104 Freiburg, Germany
[9] Albert Ludwigs Univ Freiburg, Ctr Syst Biol ZBSA, D-79104 Freiburg, Germany
[10] Columbia Univ, Dept Pathol, Med Ctr, New York, NY 10032 USA
[11] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China
基金
美国国家卫生研究院; 欧洲研究理事会;
关键词
FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RESISTANT NEPHROTIC SYNDROME; DROSOPHILA EYE; PROTEIN MAGI-1; CELL-DEATH; ADHESION; KIDNEY; GENE; EXPRESSION; JUNCTION;
D O I
10.1074/jbc.M116.745026
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
MAGI-1 is a multidomain cytosolic scaffolding protein that in the kidney is specifically located at the podocyte slit diaphragm, a specialized junction that is universally injured in proteinuric diseases. There it interacts with several essential molecules, including nephrin and nephl, which are required for slit diaphragm formation and as an intracellular signaling hub. Here, we show that diminished MAGI-1 expression in cultured podocytes reduced nephrin and nephl membrane localization and weakened tight junction integrity. Global magil knock-out mice, however, demonstrated normal glomerular histology and function into adulthood. We hypothesized that a second mild but complementary genetic insult might induce glomerular disease susceptibility in these mice. To identify such a gene, we utilized the developing fly eye to test for functional complementation between MAGI and its binding partners. In this way, we identified diminished expression of fly Hibris (nephrin) or Roughest (nephl) as dramatically exacerbating the effects of MAGI depletion. Indeed, when these combinations were studied in mice, the addition of nephrin, but not nephl, heterozygosity to homozygous deletion of MAGI-1 resulted in spontaneous glomerulosclerosis. In cultured podocytes, MAGI-1 depletion reduced intercellular contact-induced Rapl activation, a pathway critical for proper podocyte function. Similarly, magi1 knock-out mice showed diminished glomerular Rap1 activation, an effect dramatically enhanced by concomitant nephrin haploinsufficiency. Finally, combined overexpression of MAGI-1 and nephrin increased Rap 1 activation, but not when substituting a mutant MAGI-1 that cannot bind nephrin. We conclude that the interaction between nephrin and MAGI-1 regulates Rap1 activation in podocytes to maintain long term slit diaphragm structure.
引用
收藏
页码:24406 / 24417
页数:12
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