PDF(Pubmed)
Abstract：
PIKfyve is an endosomal lipid kinase that synthesizes phosphatidylinositol 3,5-biphosphate from phosphatidylinositol 3-phsphate. Inhibition of PIKfyve activity leads to lysosomal enlargement and cytoplasmic vacuolation, attributed to impaired lysosomal fission processes and homeostasis. However, the precise molecular mechanisms underlying these effects remain a topic of debate. In this study, we present findings from PIKfyve-deficient zebrafish embryos, revealing enlarged macrophages with giant vacuoles reminiscent of lysosomal storage disorders. Treatment with mTOR inhibitors or effective knockout of mTOR partially reverses these abnormalities and extend the lifespan of mutant larvae. Further in vivo and in vitro mechanistic investigations provide evidence that PIKfyve activity is essential for mTOR shutdown during early zebrafish development and in cells cultured under serum-deprived conditions. These findings underscore the critical role of PIKfyve activity in regulating mTOR signaling and suggest potential therapeutic applications of PIKfyve inhibitors for the treatment of lysosomal storage disorders.
摘要：
PIKfyve是一种内体脂质激酶，可从磷脂酰肌醇3-磷酸合成磷脂酰肌醇3,5-二磷酸。抑制PIKfyve活性导致溶酶体增大和胞质空泡化，归因于溶酶体裂变过程和稳态受损。然而,这些效应背后的确切分子机制仍然是一个争论的话题。在这项研究中,我们从缺乏PIKfyve的斑马鱼胚胎中发现，显示带有巨大液泡的肿大的巨噬细胞，让人联想到溶酶体贮积症。用mTOR抑制剂或有效敲除mTOR的治疗部分逆转了这些异常并延长了突变幼虫的寿命。进一步的体内和体外机制研究提供了证据，证明PIKfyve活性对于斑马鱼早期发育和血清剥夺条件下培养的细胞中mTOR关闭至关重要。这些发现强调了PIKfyve活性在调节mTOR信号传导中的关键作用，并提出了PIKfyve抑制剂用于治疗溶酶体贮积症的潜在治疗应用。
