Thematic review series: Lipid Posttranslational Modifications. Lysosomal metabolism of lipid-modified proteins

Jui-Yun Lu,Sandra L Hofmann

doi:10.1194/jlr.r600010-jlr200

Abstract

Much is now understood concerning the synthesis of prenylated and palmitoylated proteins, but what is known of their metabolic fate? This review details metabolic pathways for the lysosomal degradation of S-fatty acylated and prenylated proteins. Central to these pathways are two lysosomal enzymes, palmitoyl-protein thioesterase (PPT1) and prenylcysteine lyase (PCL). PPT1 is a soluble lipase that cleaves fatty acids from cysteine residues in proteins during lysosomal protein degradation. Notably, deficiency in the enzyme causes a neurodegenerative lysosomal storage disorder, infantile neuronal ceroid lipofuscinosis. PCL is a membrane-associated flavin-containing lysosomal monooxygenase that metabolizes prenylcysteine to prenyl aldehyde through a completely novel mechanism. The eventual metabolic fates of other lipidated proteins (such as glycosylphosphatidylinositol-anchored and N-myristoylated proteins) are poorly understood, suggesting directions for future research.

Highlights

Much is understood concerning the synthesis of prenylated and palmitoylated proteins, but what is known of their metabolic fate? This review details metabolic pathways for the lysosomal degradation of S-fatty acylated and prenylated proteins
The infantile form is distinguished from other forms of NCL by the characteristic electron microscopic appearance of the storage bodies, which are Abbreviations: FAD, flavin adenine dinucleotide; GPI, glycosylphosphatidylinositol; GPI-PLD, glycosylphosphatidylinositol-specific phospholipase D; GROD, granular osmiophilic deposit; INCL, infantile neuronal ceroid lipofuscinosis; MARCKS, myristoylated alanine-rich C kinase substrate; NCL, neuronal ceroid lipofuscinosis; PCL, prenylcysteine lyase; peptidylglycine aamidating monooxygenase (PGAM), peptidylglycine a-amidating monooxygenase; PPT1, palmitoyl-protein thioesterase
The role of PPT1 in the lysosomal degradation of acylated proteins has been demonstrated through metabolic labeling studies [23, 24]. [35S]cysteine labeling of cells from PPT-deficient patients leads to the accumulation of a number of hydrophobically labeled compounds containing fatty acid and cysteine; their formation is blocked by preincubation of the cells with cycloheximide, indicating that the accumulated material is derived from labeled proteins

Summary

Introduction

Much is understood concerning the synthesis of prenylated and palmitoylated proteins, but what is known of their metabolic fate? This review details metabolic pathways for the lysosomal degradation of S-fatty acylated and prenylated proteins. Only one enzyme has been described that plays a key role in the lysosomal metabolism of S-acylated proteins, a palmitoyl-protein thioesterase (PPT1). PPT1 (EC 3.1.2.22; known as palmitoyl-protein hydrolase) is a lysosomal enzyme that removes fatty acids from their covalent thioester linkage to cysteine residues in S-acylated proteins.

Results

Conclusion