The awesome lysosome

Abstract

In the early 50s, Christian De Duve identified a new cellular structure, the lysosome, defined as the cell's “suicide bag” (de Duve, 2005). Sixty years later, it is clear that the lysosome greatly exceeded the expectations of its discoverer. Over 50 different types of lysosomal storage diseases have been identified, each due to the deficiency or malfunction of a specific lysosomal protein. In addition, an important role of the lysosome has been unveiled in several common human diseases, such as cancer, obesity, neurodegenerative diseases, and infection. Recent studies have led to the identification of a lysosome‐to‐nucleus signaling pathway and a lysosomal gene network that regulate cellular clearance and energy metabolism. These observations have opened a completely new field of research and changed our traditional view of the lysosome from a dead‐end organelle to a control center of cell metabolism. An important challenge for the future will be to exploit these discoveries to identify modulators of lysosomal function that may be used to treat human diseases.

Figure 1. TFEB‐mediated cellular clearance

TFEB overexpression promotes cellular clearance in mouse models of human diseases. Representative figures from published studies demonstrating clearance of accumulating substrates in LSDs, Parkinson's, Alzheimer's, and Huntington's diseases, α1‐anti‐trypsin deficiency, and spinal bulbar muscular atrophy. The asterisks indicate the papers in which the original images were published.

Figure 2. A lysosome‐to‐nucleus signaling mechanism

Signaling mechanisms that regulate TFEB nuclear translocation. Under normal feeding conditions, TFEB is phosphorylated by mTORC1 on the lysosomal surface and is sequestered in the cytoplasm by 14‐3‐3 proteins. During starvation and physical exercise mTORC1 is inactivated and Ca²⁺ is released from the lysosome through MCOLN1. This leads to local calcineurin activation and TFEB dephosphorylation. Dephosphorylated TFEB is no longer able to bind 14‐3‐3 proteins and can freely translocate to the nucleus where it transcriptionally activates the lysosomal/autophagic pathway [modified from (Medina et al, 2015)].