Vps34/PI3KC3 deletion in kidney proximal tubules impairs apical trafficking and blocks autophagic flux, causing a Fanconi-like syndrome and renal insufficiency.
Vps34/PI3KC3 deletion in kidney proximal tubules impairs apical trafficking and blocks autophagic flux, causing a Fanconi-like syndrome and renal insufficiency.
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DOI：
10.1038/s41598-018-32389-z
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发表时间：
2018-09-20
影响因子：
4.6
通讯作者：
Courtoy PJ
中科院分区：
文献类型：
--
作者：
Grieco G;Janssens V;Gaide Chevronnay HP;N'Kuli F;Van Der Smissen P;Wang T;Shan J;Vainio S;Bilanges B;Jouret F;Vanhaesebroeck B;Pierreux CE;Courtoy PJ
肾近端小管细胞（PTC）是高度特化的超滤液重吸收细胞，并作为顶端上皮分化的范例。Vps 34/PI 3-激酶III型（PI 3 KC 3）调节内体动力学、大自噬和溶酶体功能。然而，其在PTC中的体内作用尚未被评估。通过Pax 8-Cre在PTC中条件性缺失Vps 34/PI 3 KC 3导致早期（P7）PTC功能障碍，表现为Fanconi样综合征，随后是肾衰竭（P14）和死亡。通过共聚焦显微镜，Vps 34 α/β PTCs显示保留的顶端-基底特化（刷状缘，NHERF-1与Na+/K+-ATP酶，锚蛋白-G），但晚期内体/溶酶体（LAMP-1）的基底再分布以及顶端再循环内吞受体（megalin，cubilin）和顶端非再循环溶质载体（NaPi-IIa，SGLT-2）的溶酶体错误定位。通过德克萨斯红-卵清蛋白示踪和白蛋白含量降低证实了内吞缺陷。Rab-11和核周半乳糖凝集素-3区室的破坏提出了缺陷受体回收和顶端生物合成贩运的机制线索。p62依赖性自噬被触发但失败（p62与LC 3共定位，但不与LAMP-1共定位），PTC变得空泡化。溶酶体定位受损和自噬受阻是细胞应激的已知原因。因此，早期运输缺陷表明，Vps 34是一个关键的体内分子机制，管理顶端囊泡运输，因此在PTC的吸收功能。功能缺陷强调了Vps 34对PTC稳态和肾存活的重要作用。
Kidney proximal tubular cells (PTCs) are highly specialized for ultrafiltrate reabsorption and serve as paradigm of apical epithelial differentiation. Vps34/PI3-kinase type III (PI3KC3) regulates endosomal dynamics, macroautophagy and lysosomal function. However, its in vivo role in PTCs has not been evaluated. Conditional deletion of Vps34/PI3KC3 in PTCs by Pax8-Cre resulted in early (P7) PTC dysfunction, manifested by Fanconi-like syndrome, followed by kidney failure (P14) and death. By confocal microscopy, Vps34∆/∆ PTCs showed preserved apico-basal specification (brush border, NHERF-1 versus Na+/K+-ATPase, ankyrin-G) but basal redistribution of late-endosomes/lysosomes (LAMP-1) and mis-localization to lysosomes of apical recycling endocytic receptors (megalin, cubilin) and apical non-recycling solute carriers (NaPi-IIa, SGLT-2). Defective endocytosis was confirmed by Texas-red-ovalbumin tracing and reduced albumin content. Disruption of Rab-11 and perinuclear galectin-3 compartments suggested mechanistic clues for defective receptor recycling and apical biosynthetic trafficking. p62-dependent autophagy was triggered yet abortive (p62 co-localization with LC3 but not LAMP-1) and PTCs became vacuolated. Impaired lysosomal positioning and blocked autophagy are known causes of cell stress. Thus, early trafficking defects show that Vps34 is a key in vivo component of molecular machineries governing apical vesicular trafficking, thus absorptive function in PTCs. Functional defects underline the essential role of Vps34 for PTC homeostasis and kidney survival.
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DOI：
10.1083/jcb.201611073
发表时间：
2017-12-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hong Z;Pedersen NM;Wang L;Torgersen ML;Stenmark H;Raiborg C
通讯作者：
Raiborg C
影响因子：
4.5
作者：
Carpentier, Sarah;N'Kuli, Francisca;Courtoy, Pierre J.
通讯作者：
Courtoy, Pierre J.
影响因子：
13.6
作者：
Amsellem, Sabine;Gburek, Jakub;Kozyraki, Renata
通讯作者：
Kozyraki, Renata
影响因子：
8.8
作者：
Alliouachene S;Bilanges B;Chicanne G;Anderson KE;Pearce W;Ali K;Valet C;Posor Y;Low PC;Chaussade C;Scudamore CL;Salamon RS;Backer JM;Stephens L;Hawkins PT;Payrastre B;Vanhaesebroeck B
通讯作者：
Vanhaesebroeck B
影响因子：
3.3
作者：
Cao, Canhong;Backer, Jonathan M.;Wandinger-Ness, Angela
通讯作者：
Wandinger-Ness, Angela