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Cystinosin is a Component of the Vacuolar H+-ATPase-Ragulator-Rag Complex
Controlling Mammalian Target of Rapamycin Complex 1 Signaling
#MMPMID26449607
Andrzejewska Z
; Nevo N
; Thomas L
; Chhuon C
; Bailleux A
; Chauvet V
; Courtoy PJ
; Chol M
; Guerrera IC
; Antignac C
J Am Soc Nephrol
2016[Jun]; 27
(6
): 1678-88
PMID26449607
show ga
Cystinosis is a rare autosomal recessive storage disorder characterized by
defective lysosomal efflux of cystine due to mutations in the CTNS gene encoding
the lysosomal cystine transporter, cystinosin. Lysosomal cystine accumulation
leads to crystal formation and functional impairment of multiple organs.
Moreover, cystinosis is the most common inherited cause of renal Fanconi syndrome
in children. Oral cysteamine therapy delays disease progression by reducing
intracellular cystine levels. However, because cysteamine does not correct all
complications of cystinosis, including Fanconi syndrome, we hypothesized that
cystinosin could have novel roles in addition to transporting cystine out of the
lysosome. By coimmunoprecipitation experiments and mass spectrometry, we found
cystinosin interacts with almost all components of vacuolar H(+)-ATPase and the
Ragulator complex and with the small GTPases Ras-related GTP-binding protein A
(RagA) and RagC. Furthermore, the mammalian target of rapamycin complex 1
(mTORC1) pathway was downregulated in proximal tubular cell lines derived from
Ctns(-/-) mice. Decrease of lysosomal cystine levels by cysteamine did not rescue
mTORC1 activation in these cells, suggesting that the downregulation of mTORC1 is
due to the absence of cystinosin rather than to the accumulation of cystine. Our
results show a dual role for cystinosin as a cystine transporter and as a
component of the mTORC1 pathway, and provide an explanation for the appearance of
Fanconi syndrome in cystinosis. Furthermore, this study highlights the need to
develop new treatments not dependent on lysosomal cystine depletion alone for
this devastating disease.
|*Signal Transduction
[MESH]
|Amino Acid Transport Systems, Neutral/*physiology
[MESH]
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free
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