Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation
Jaerak Chang, … , Seongju Lee, Craig Blackstone
Jaerak Chang, … , Seongju Lee, Craig Blackstone
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(12):5249-5262. https://doi.org/10.1172/JCI77598.
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Research Article Neuroscience

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation

Abstract

Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.

Authors

Jaerak Chang, Seongju Lee, Craig Blackstone

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Figure 11

Model of effects of spastizin and spatacsin loss in ALR.

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Model of effects of spastizin and spatacsin loss in ALR. (A) In control ...
(A) In control cells, autophagosomes containing autophagic materials fuse with the lysosome to form the autolysosome. After degrading materials, the lysosomal tubule emanates from the autolysosome and becomes the protolysosome, which is destined to become a lysosome after maturation. This machinery for maintaining the population of cellular lysosomes is called ALR. In cells from patients with SPG15 or SPG11, fusion of the lysosome and the autophagosome occurs normally, but ALR is blocked by impaired initiation of lysosomal tubulation from the autolysosome, which eventually results in accumulation of autolysosomes and exhaustion of free lysosomes. (B) Schematic model of lysosome reformation in starvation and feeding conditions. In feeding conditions, basal autophagy occurs to maintain cell homeostasis. At autolysosomes, PI4KB plays a critical role by converting phosphatidylinositol (PI) to PI(4)P, which suppresses uncontrolled lysosomal tubulation from autolysosomes and facilitates lysosome budding/vesiculation managed by clathrin (or other coat proteins) and Dyn2, reminiscent of endocytosis. The spastizin-spatacsin complex localizes to the lysosome/autolysosome by interaction of the spastizin FYVE domain and PI(3)P, and this complex is also an essential component for lysosome vesiculation. In prolonged starvation conditions, to rapidly generate energy sources cells choose an enhanced pathway, ALR, which reforms lysosomes more efficiently. In this case, PI(4,5)P2 produced from PI(4)P by PIP5K1B is an essential component for tubule initiation. The spastizin-spatacsin complex may function downstream of PI(4,5)P2 or work independently during ALR. The AP-5 protein complex that coprecipitates with spastizin and spatacsin is not shown.