A lysosomal proteinase, the late infantile neuronal ceroid lipofuscinosis gene (CLN2) product, is essential for degradation of a hydrophobic protein, the subunit c of ATP synthase - PubMed (original) (raw)

A lysosomal proteinase, the late infantile neuronal ceroid lipofuscinosis gene (CLN2) product, is essential for degradation of a hydrophobic protein, the subunit c of ATP synthase

J Ezaki et al. J Neurochem. 1999 Jun.

Free article

Abstract

The specific accumulation of the hydrophobic protein, subunit c of ATP synthase, in lysosomes from the cells of patients with the late infantile form of neuronal ceroid lipofuscinosis (LINCL) is caused by lysosomal proteolytic dysfunction. The defective gene in LINCL (CLN2 gene) has been identified recently. To elucidate the mechanism of lysosomal storage of subunit c, antibodies against the human CLN2 gene product (Cln2p) were prepared. Immunoblot analysis indicated that Cln2p is a 46-kDa protein in normal control skin fibroblasts and carrier heterozygote cells, whereas it was absent in cells from four patients with LINCL. RT-PCR analysis indicated the presence of mRNA for CLN2 in cells from the four different patients tested, suggesting a low efficiency of translation of mRNA or the production of the unstable translation products in these patient cells. Pulse-chase analysis showed that Cln2p was synthesized as a 67-kDa precursor and processed to a 46-kDa mature protein (t(1/2) = 1 h). Subcellular fractionation analysis indicated that Cln2p is localized with cathepsin B in the high-density lysosomal fractions. Confocal immunomicroscopic analysis also revealed that Cln2p is colocalized with a lysosomal soluble marker, cathepsin D. The immunodepletion of Cln2p from normal fibroblast extracts caused a loss in the degradative capacity of subunit c, but not the beta subunit of ATP synthase, suggesting that the absence of Cln2p provokes the lysosomal accumulation of subunit c.

PubMed Disclaimer

Cited by

Brain transcriptome analysis of a CLN2 mouse model as a function of disease progression.
Domowicz MS, Chan WC, Claudio-Vázquez P, Gonzalez T, Schwartz NB. Domowicz MS, et al. J Neuroinflammation. 2021 Nov 8;18(1):262. doi: 10.1186/s12974-021-02302-z. J Neuroinflammation. 2021. PMID: 34749772 Free PMC article.
Lysosomal serine protease CLN2 regulates tumor necrosis factor-alpha-mediated apoptosis in a Bid-dependent manner.
Autefage H, Albinet V, Garcia V, Berges H, Nicolau ML, Therville N, Altié MF, Caillaud C, Levade T, Andrieu-Abadie N. Autefage H, et al. J Biol Chem. 2009 Apr 24;284(17):11507-16. doi: 10.1074/jbc.M807151200. Epub 2009 Feb 26. J Biol Chem. 2009. PMID: 19246452 Free PMC article.
Different molecular mechanisms involved in spontaneous and oxidative stress-induced mitochondrial fragmentation in tripeptidyl peptidase-1 (TPP-1)-deficient fibroblasts.
Van Beersel G, Tihon E, Demine S, Hamer I, Jadot M, Arnould T. Van Beersel G, et al. Biosci Rep. 2013 Feb 7;33(2):e00023. doi: 10.1042/BSR20120104. Biosci Rep. 2013. PMID: 23249249 Free PMC article.
A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer.
Bajaj L, Sharma J, di Ronza A, Zhang P, Eblimit A, Pal R, Roman D, Collette JR, Booth C, Chang KT, Sifers RN, Jung SY, Weimer JM, Chen R, Schekman RW, Sardiello M. Bajaj L, et al. J Clin Invest. 2020 Aug 3;130(8):4118-4132. doi: 10.1172/JCI130955. J Clin Invest. 2020. PMID: 32597833 Free PMC article.
Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B.
Ryazantsev S, Yu WH, Zhao HZ, Neufeld EF, Ohmi K. Ryazantsev S, et al. Mol Genet Metab. 2007 Apr;90(4):393-401. doi: 10.1016/j.ymgme.2006.11.006. Epub 2006 Dec 20. Mol Genet Metab. 2007. PMID: 17185018 Free PMC article.

A lysosomal proteinase, the late infantile neuronal ceroid lipofuscinosis gene (CLN2) product, is essential for degradation of a hydrophobic protein, the subunit c of ATP synthase - PubMed (original) (raw)