Ivanova Ekaterina A, van den Heuvel Lambertus P, Elmonem Mohamed A, De Smedt Humbert, Missiaen Ludwig, Pastore Anna, Mekahli Djalila, Bultynck Greet, Levtchenko Elena N
Department of Growth and Regeneration, KU Leuven and University Hospitals Leuven, UZ Herestraat 49, 3000, Leuven, Belgium.
Department of Pediatric Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.
J Inherit Metab Dis. 2016 May;39(3):457-464. doi: 10.1007/s10545-016-9919-z. Epub 2016 Feb 24.
Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades.
溶酶体通过激活雷帕霉素哺乳动物靶蛋白复合物1（mTORC1）在自噬调节中发挥核心作用。我们研究了溶酶体贮积病肾病性胱氨酸病（MIM 219800）中的mTORC1信号传导，此前已证明该病存在自噬标志物的积累。胱氨酸病由溶酶体胱氨酸转运体胱氨酸转运蛋白的突变引起，最初影响肾近端小管，导致肾性范科尼综合征，随后逐渐发展为终末期肾病和肾外并发症。使用从健康供体和胱氨酸病患者获得的近端肾小管细胞，我们证明胱氨酸转运蛋白缺乏与mTORC1信号传导紊乱、饥饿后mTORC1的重新激活延迟以及饥饿期间mTOR在溶酶体中的异常滞留有关。用耗竭胱氨酸的药物半胱胺治疗无法逆转这些影响。mTORC1信号传导的改变可能导致胱氨酸病中近端肾小管功能障碍的发展，并指出通过调节mTORC依赖性信号级联进行治疗干预的新可能性。
