Membrane Resealing Mediated by Lysosomal Exocytosis

Abstract

Ca²⁺-regulated exocytosis was proposed to mediate plasma membrane repair, but until recently the nature of the vesicles involved was unknown. Recent work from our laboratory identified lysosomes as the intracellular organelles responsible for this process. Ca²⁺ triggers the exocytosis of conventional lysosomes, and this process is regulated by a ubiquitously expressed synaptotagmin, Syt VII. Dominant-negative or gene deletion approaches revealed that Syt VII is required for normal lysosomal exocytosis and membrane resealing. Cells from Syt VII-deficient mice show defects in lysosomal exocytosis and membrane repair, and the animals develop a form of autoimmune myopathy similar to the human diseases polymyositis/dermatomyositis.

Secretion of lysosomal enzymes is a common physiological event, often observed in a variety of tissues. Lysosomes, however, have been traditionally regarded as “terminal” compartments, the final site of accumulation of endocytosed macromolecules. This concept is derived mostly from the fact that lysosomes do not constitutively recycle to the plasma membrane, in contrast to what is observed with early endosomes. The norm thus became to interpret lysosomal enzyme secretion as a result of altered sorting pathways: the enzymes would be diverted at the level of the trans-Golgi network into “classical” Ca²⁺-regulated secretory granules. However, in several cases there is no direct evidence that lysosomal enzymes colocalize with “classical” secretory products inside specialized granules. And as further discussed in this chapter, many cell types that lack “classical” secretory granules secrete lysosomal enzymes when stimulated. Therefore, it is conceivable that a significant fraction of the observations previously interpreted as alterations in lysosomal enzyme sorting are a consequence of direct exocytosis of conventional lysosomes. In “professional” regulated secretory cells, conventional lysosomes may be secreted in parallel with “classical” granules, since the [Ca²⁺]_i elevation induced by a secretagogue can trigger both processes (Fig. 1). We discuss below recent evidence suggesting that this pathway of conventional lysosome exocytosis has an important role in plasma membrane repair.