The Biology of Lysosomes: From Order to Disorder

Abstract

Since its discovery in 1955, the understanding of the lysosome has continuously increased. Once considered a mere waste removal system, the lysosome is now recognised as a highly crucial cellular component for signalling and energy metabolism. This notable evolution raises the need for a summarized review of the lysosome's biology. As such, throughout this article, we will be compiling the current knowledge regarding the lysosome's biogenesis and functions. The comprehension of this organelle's inner mechanisms is crucial to perceive how its impairment can give rise to lysosomal disease (LD). In this review, we highlight some examples of LD fine-tuned mechanisms that are already established, as well as others, which are still under investigation. Even though the understanding of the lysosome and its pathologies has expanded through the years, some of its intrinsic molecular aspects remain unknown. In order to illustrate the complexity of the lysosomal diseases we provide a few examples that have challenged the established single gene-single genetic disorder model. As such, we believe there is a strong need for further investigation of the exact abnormalities in the pathological pathways in lysosomal disease.

Keywords: endocytic pathway; lysosomal disease; lysosome; lysosome biogenesis and function.

Figure 1

The lysosomal biosynthetic and endocytic pathways. Under starvation, TFEB is translocated to the nucleus and binds genes coding for lysosomal proteins, upregulating protein synthesis and initiating the biosynthetic pathway (purple arrows). Proteins are transported to the ER lumen. The proteins then travel to the cis-Golgi, some proteins require a membrane protein for this transport, like the β-Glucocerebrosidase (GCase) LIMP-2 mediated-transport (green arrows). In the cis-Golgi, the uncovering enzyme uncovers the mannose 6-phosphate (M6P) sugar in lysosomal proteins. Lysosomal proteins then arrive to the TGN, where Mannose 6-phosphate receptors (M6PR) recognize the M6P tag and are packed into clathrin-coated vesicles. Lysosomal proteins reach early endosomes (EE) and dissociate from M6PR and remain in the endosomal lumen. The M6PR can be recycled, returning to the TGN by the endosome to TGN carriers (yellow arrows). Endosomal intermediates transport the lysosomal proteins to the lysosomes through the endocytic pathway (pink arrows). Other proteins that don’t have specific target characteristics, may follow the constitutive secretory pathway to the plasma membrane (blue arrows) and reach lysosomes by endocytosis. VSE—vacuolar sorting endosome; ILVs—intraluminal vesicles; TSE—tubular sorting endosome.

Figure 2

Examples of lysosomal hydrolase deficiency. In (A), the mutated hydrolase is not able to pair with the transporter and consequently is not able to reach the lysosome. In (B), the mutated hydrolase is carried to the lysosome through the M6P pathway or through the LIMP-2 pathway but is not able to degrade, leading to substrate accumulation in the lysosome.