Abstract
btn1, the Schizosaccharomyces pombe orthologue of the human Batten-disease gene CLN3, is involved in vacuole pH homeostasis. We show that loss of btn1 also results in a defective cell wall marked by sensitivity to zymolyase, a beta-glucanase. The defect can be rescued by expression of Btn1p or CLN3, and the extent of the defect correlates with disease severity. The vacuole and cell-wall defects are linked by a common pH-dependent mechanism, because they are suppressed by growth in acidic pH and a similar glucan defect is also apparent in the V-type H(+) ATPase (v-ATPase) mutants vma1Delta and vma3Delta. Significantly, Btn1p acts as a multicopy suppressor of the cell-wall and other vacuole-related defects of these v-ATPase-null cells. In addition, Btn1p is required in a second, pH-independent, process that affects sites of polarised growth and of cell-wall deposition, particularly at the septum, causing cytokinesis problems under normal growth conditions and eventual cell lysis at 37 degrees C. Thus, Btn1p impacts two independent processes, which suggests that Batten disease is more than a pH-related lysosome disorder.
Highlights
Juvenile-onset neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a severe neurodegenerative lysosomal-storage disorder of childhood that is characterised by accumulation of lipofuscinlike material and is caused by an intragenic mutation in CLN3 (The International Batten Disease Consortium, 1995; Kitzmüller et al, 2008; Santavuori, 1988)
We monitored the septation index of cells grown in yeast extract with supplements (YES) at 25°C, and found that 22% of btn1Δ cells were in the process of septation, compared with 8.6% for wild-type cells (Fig. 1A)
Defective acidification of the endocytic system can cause a cell-wall defect Given that, at 25°C, cells deleted for btn1 have an aberrant cell wall and cytokinesis defects, as well as defective vacuole acidification (Gachet et al, 2005), we explored whether, in S. pombe, an increased endocytic and/or vacuole pH might be the cause of the described defects in the cell wall
Summary
Juvenile-onset neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is a severe neurodegenerative lysosomal-storage disorder of childhood that is characterised by accumulation of lipofuscinlike material and is caused by an intragenic mutation in CLN3 (The International Batten Disease Consortium, 1995; Kitzmüller et al, 2008; Santavuori, 1988). CLN3, a transmembrane protein (Kyttälä et al, 2004; Nugent et al, 2008), has no homology with other proteins or functional domains and its function is unknown. In mammalian cells, this protein has been connected with lysosome homeostasis (Holopainen et al, 2001; RamirezMontealegre and Pearce, 2005). Disease caused by complete lack of CLN3 function has not yet been described (Kitzmüller et al, 2008)
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