Lysosomal enzyme targeting.

Historical overview I want to express my appreciation to the Biochemical Society for having invited me to deliver the 1989 Jubilee Lecture. It is truly a great honour. The word Jubilee connotes a very special anniversary, and in this spirit I want to impart an historical overview to the Lecture in addition to reviewing my most recent work. This is especially appropriate because my work on lysosomal enzyme targeting has built on the remarkable achievements of previous investigators in this field. It is almost 40 years since the classic studies of Christian DeDuve and his colleagues resulted in the discovery of lysosomes as a special group of cytoplasmic particles that contained numerous acid-dependent hydrolases [ 11. This early work is described in Dr DeDuve’s Jubilee Lecture given in 1978 [ 2 ] . After these seminal observations, there was a flurry of studies by DeDuve, Straus, Novikoff, Cohn, Tappel and others which established that lysosomes are responsible for degrading both internalized and endogenous macromolecules. These early studies were summarized in a wonderful Ciba Foundation Symposium which was published in 1963 [3]. That same year Hers reported the first case of a lysosomal storage disease, thereby initiating a new chapter in the study of this organelle [4]. At the present time more than 40 different lysosomal storage diseases have been described. Most of these disorders are characterized by a deficiency of a single lysosomal enzyme which results in a massive accumulation of the material that is normally degraded by that enzyme. It was studies of cultured fibroblasts from patients with genetic disorders of mucopolysaccharide catabolism that initiated the next phase of research in this field, which was the investigation of the biogenesis of lysosomes. In a series of insightful experiments, Elizabeth Neufeld and her colleagues observed that normal fibroblasts secrete ‘corrective factors’ that are rapidly endocytosed by enzyme-deficient cells, resulting in the degradation of the accumulated mucopolysaccharides [S]. When these corrective factors were purified, they were found to be the particular lysosomal enzymes that were missing in the various mutant fibroblasts. Neufeld also noted that the lysosomal enzymes were taken up in a selective and saturable manner, indicating that they contained a recognition marker that allowed high-affinity binding to receptors on the fibroblast surface. Evidence for the presence of a common recognition marker came from studies of patients with I-cell disease (mucolipidosis ll), a rare autosomal recessive disorder characterized by the intracellular deficiency of many lysosomal enzymes in the face of elevated levels of these enzymes in the patient’s plasma. Hickman & Neufeld observed that fibroblasts from I-cell patients take up and retain normal lysosomal enzymes in the usual fashion, whereas similar hydrolases secreted by I-cell fibroblasts are not taken up by normal fibroblasts [6]. This led the authors to propose that the enzymes secreted by the I-cell fibroblasts lack a recognition marker required for adsorptive pinocytosis. Subsequent studies indicated that the oligosaccharides on acid hydrolases were involved in the recognition by the cell surface receptors [7, 81, but the identity of the functional group remained obscure until Kaplan et al. demonstrated that the adsorptive pinocytosis of Jubilee Lecture Delivered on 19 December 1989 at St Bartholomew’s Hospital Medical College, London