No abstract

Lysosomes are dynamic organelles that undergo cycles of fusion and fission with themselves and with other organelles. Following fusion with late endosomes to form hybrid organelles, lysosomes are reformed as discrete organelles. This lysosome reformation or formation is a poorly understood process that has not been systematically analyzed and that lacks known regulators. In this study, we quantitatively define the multiple steps of lysosome formation and identify the first regulator of this process.

Lysosomes, the major membrane-bound degradative organelles, have a multitude of functions in eukaryotic cells. Lysosomes are the terminal compartments in the endocytic pathway, though they display highly dynamic behaviors, fusing with each other and with late endosomes in the endocytic pathway, and with the plasma membrane during regulated exocytosis and for wound repair. After fusing with late endosomes, lysosomes are reformed from the resulting hybrid organelles through a process that involves budding of a nascent lysosome, extension of the nascent lysosome from the hybrid organelle, while remaining connected by a membrane bridge, and scission of the membrane bridge to release the newly formed lysosome. The newly formed lysosomes undergo cycles of homotypic fusion and fission reactions to form mature lysosomes. In this study, we used a forward genetic screen in Caenorhabditis elegans to identify six regulators of lysosome biology. We show that these proteins function in different steps of lysosome biology, regulating lysosome formation, lysosome fusion, and lysosome degradation.

Identifying immune factors associated with the development of atopy can enhance our understanding of the in vivo mechanisms involved and may have utility in paradigms designed to prevent disease. Two candidates suggested for such roles are the soluble low affinity receptor for IgE (sCD23) and the soluble interleukin-2 receptor (sCD25). To assess serum levels of these factors blood samples were collected at birth and at age 6 in a large nonselected population from Tucson, AZ. Log mean sCD23 and sCD25 levels decreased from birth to age 6, (for sCD23 0.60 ffi 0.26pg/l, n = 340 and 0.53 + 0.28pg/l, n = 333 and for sCD25 1.95 i 0.14pM, n = 304 and 1.86 ffi 0.20pM, n = 327, for the two ages respectively. Anglo children had lower sCD23 levels at birth compared to Hispanic children (p < 0.01); no effect of gender was observed. Skin test reactivity at age 6 was directly related to sCD25 levels at age 6 (p = 0.007) and even levels at birth showed a similar trend (p = 0.06). These relations were distinct from any relation to total serum IgE. No relation was observed with sCD23 levels for either skin test reactivity or serum IgE. The prevalences of asthma, rhinitis and eczema by age 6 were unrelated to sCD25 or sCD23 levels. The results indicate that soluble CD23 and CD25 have higher levels at birth than later in childhood and that the development of skin test reactivity may be associated with regulatory mechanisms involving sCD25, whereas sCD23 was not similarly implicated.