Lysosomal Targeting of Palmitoyl-protein Thioesterase

Verkruyse, Linda A.; Hofmann, Sandra L.

doi:10.1074/jbc.271.26.15831

Cited by 229 publications

(152 citation statements)

References 27 publications

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“…Each of the three identified proteins whose deficiency results in NCL are localized within the lysosome [4,[6][7][8][9]. Whereas the CLN3 protein seems to be a transmembrane lysosomal protein [5,10], the CLN2 protease and palmitoyl-protein thioesterase are soluble lysosomal enzymes.…”

Section: Introductionmentioning

confidence: 99%

Specific alterations in levels of mannose 6-phosphorylated glycoproteins in different neuronal ceroid lipofuscinoses

Sleat

Sohár

Pullarkat³

et al. 1998

Biochemical Journal

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Mannose 6-phosphate (Man-6-P) is a carbohydrate modification that is generated on newly synthesized lysosomal proteins. This modification is specifically recognized by two Man-6-P receptors that direct the vesicular transport of the lysosomal enzymes from the Golgi to a prelysosomal compartment. The Man-6-P is rapidly removed in the lysosome of most cell types; however, in neurons the Man-6-P modification persists. In this study we have examined the spectrum of Man-6-P-containing glycoproteins in brain specimens from patients with different neuronal ceroid lipofuscinoses (NCLs), which are progressive neurodegenerative disorders with established links to defects in lysosomal catabolism. We find characteristic alterations in the Man-6-P glycoproteins in specimens from late-infantile (LINCL), juvenile (JNCL) and adult (ANCL) patients. Man-6-P glycoproteins in LINCL patients were similar to controls, with the exception that the band corresponding to CLN2, a recently identified lysosomal enzyme whose deficiency results in this disease, was absent. In an ANCL patient, two Man-6-P glycoproteins were elevated in comparison with normal controls, suggesting that this disease also results from a perturbation in lysosomal hydrolysis. In JNCL, total levels of Man-6-P glycoproteins were 7-fold those of controls. In general this was reflected by increased lysosomal enzyme activities in JNCL but three Man-6-P glycoproteins were elevated to an even greater degree. These are CLN2 and the unidentified proteins that are also highly elevated in the ANCL.

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Section: Introductionmentioning

confidence: 99%

Specific alterations in levels of mannose 6-phosphorylated glycoproteins in different neuronal ceroid lipofuscinoses

Sleat

Sohár

Pullarkat³

et al. 1998

Biochemical Journal

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“…However, the purification of palmitoylating enzymes (Dunphy et al, 1996;Lui et al, 1996) (Verkruyse and Hofman, 1996).…”

Section: Cell-free Palmitoylation Of Tubulinmentioning

confidence: 99%

Posttranslational modification of tubulin by palmitoylation: I. In vivo and cell-free studies.

Caron

1997

MBoC

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It is well established that microtubules interact with intracellular membranes of eukaryotic cells. There is also evidence that tubulin, the major subunit of microtubules, associates directly with membranes. In many cases, this association between tubulin and membranes involves hydrophobic interactions. However, neither primary sequence nor known posttranslational modifications of tubulin can account for such an interaction. The goal of this study was to determine the molecular nature of hydrophobic interactions between tubulin and membranes. Specifically, I sought to identify a posttranslational modification of tubulin that is found in membrane proteins but not in cytoplasmic proteins. One such modification is the covalent attachment of the long chain fatty acid palmitate. The possibility that tubulin is a substrate for palmitoylation was investigated. First, I found that tubulin was palmitoylated in resting platelets and that the level of palmitoylation of tubulin decreased upon activation of platelets with thrombin. Second, to obtain quantities of palmitoylated tubulin required for protein structure analysis, a cell-free system for palmitoylation of tubulin was developed and characterized. The substrates for palmitoylation were nonpolymerized tubulin and tubulin in microtubules assembled with the slowly hydrolyzable GTP analogue guanylyl-(a,3)-methylenediphosphonate. However, tubulin in Taxol-assembled microtubules was not a substrate for palmitoylation. Likewise, palmitoylation of tubulin in the cell-free system was specifically inhibited by the antimicrotubule drugs Colcemid, podophyllotoxin, nocodazole, and vinblastine. These experiments identify a previously unknown posttranslational modification of tubulin that can account for at least one type of hydrophobic interaction with intracellular membranes.

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“…Two of these thioesterases, acyl-protein thioesterase-1 (APT1) (11) and APT2 (12), are localized predominantly in the cytoplasm, and the other two, palmitoyl-protein thioesterase-1 (PPT1) (13,14) and PPT2 (15), are lysosomal enzymes (16,17). The first cytosolic thioesterase to be characterized was APT1, which cat-alyzed depalmitoylation of the ␣-subunit of G-proteins and proto-oncogene H-Ras product in vitro (11) as well as synaptosomal-associated protein 23 (SNAP-23) (18).…”

mentioning

confidence: 99%

Dynamic Palmitoylation Links Cytosol-Membrane Shuttling of Acyl-protein Thioesterase-1 and Acyl-protein Thioesterase-2 with That of Proto-oncogene H-Ras Product and Growth-associated Protein-43

Kong

Peng

Chandra

et al. 2013

Journal of Biological Chemistry

117

146

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Background: How cytosolic thioesterases (APT1 and APT2) depalmitoylate their membrane-anchored substrates remains unclear. Results: APT1 and APT2 require palmitoylation for membrane localization. Although APT1 depalmitoylates itself, H-Ras, and APT2, APT2 depalmitoylates GAP-43. Conclusion: Dynamic palmitoylation regulates steady-state membrane localization and function of cytosolic thioesterases and their substrates. Significance: The findings may provide new insight into the regulation and function of cytosolic thioesterases and their substrates.

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Lysosomal Targeting of Palmitoyl-protein Thioesterase

Cited by 229 publications

References 27 publications

Specific alterations in levels of mannose 6-phosphorylated glycoproteins in different neuronal ceroid lipofuscinoses

Specific alterations in levels of mannose 6-phosphorylated glycoproteins in different neuronal ceroid lipofuscinoses

Posttranslational modification of tubulin by palmitoylation: I. In vivo and cell-free studies.

Dynamic Palmitoylation Links Cytosol-Membrane Shuttling of Acyl-protein Thioesterase-1 and Acyl-protein Thioesterase-2 with That of Proto-oncogene H-Ras Product and Growth-associated Protein-43

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