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Review
. 2022 Oct;12(10):220155.
doi: 10.1098/rsob.220155. Epub 2022 Oct 26.

Lysosomal positioning diseases: beyond substrate storage

Gianluca Scerra  1 , Valeria De Pasquale  2 , Melania Scarcella  1 , Maria Gabriella Caporaso  1 , Luigi Michele Pavone  1 , Massimo D'Agostino  1
Affiliations
Review

Lysosomal positioning diseases: beyond substrate storage

Gianluca Scerra et al. Open Biol. 2022 Oct.

Abstract

Lysosomal storage diseases (LSDs) comprise a group of inherited monogenic disorders characterized by lysosomal dysfunctions due to undegraded substrate accumulation. They are caused by a deficiency in specific lysosomal hydrolases involved in cellular catabolism, or non-enzymatic proteins essential for normal lysosomal functions. In LSDs, the lack of degradation of the accumulated substrate and its lysosomal storage impairs lysosome functions resulting in the perturbation of cellular homeostasis and, in turn, the damage of multiple organ systems. A substantial number of studies on the pathogenesis of LSDs has highlighted how the accumulation of lysosomal substrates is only the first event of a cascade of processes including the accumulation of secondary metabolites and the impairment of cellular trafficking, cell signalling, autophagic flux, mitochondria functionality and calcium homeostasis, that significantly contribute to the onset and progression of these diseases. Emerging studies on lysosomal biology have described the fundamental roles of these organelles in a variety of physiological functions and pathological conditions beyond their canonical activity in cellular waste clearance. Here, we discuss recent advances in the knowledge of cellular and molecular mechanisms linking lysosomal positioning and trafficking to LSDs.

Keywords: lysosomal storage diseases; lysosome; membrane contact sites; microtubule tracks; positioning; trafficking.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
The bidirectional movement of endolysosomes on microtubule tracks is driven by different macromolecular complexes. (a) The kinesin adaptor FYCO1 interacts with active Rab7 and PI(3)P on the lysosomal membrane to recruit kinesin-1 to the lysosomal surface. (b) The lysosomal multi-subunit complex BORC allows the recruitment of the small GTPase Arl8 to lysosomes. Arl8 recruits the effector protein SKIP to bind kinesin-1 motor protein. (c) The small GTPase Rab7 recruits the effector protein RILP and the dynein–dynactin motor on the lysosomal surface. (d) The role of Ca2+ in endolysosomal positioning. High levels of PI(3,5)P2 on endolysosomal membranes stimulate the opening of the TRPML1 channel to promote Ca2+ efflux which allows the recruitment of calcium sensor ALG2 at the endolysosomal membranes. Then, ALG2 recruits the dynein–dynactin complex to TRPML1-containing lysosomes. (e) Under nutrients or cholesterol depletion conditions, the lysosomal transmembrane protein TMEM55B is upregulated and promotes interaction with dynein through the adaptor protein JIP4. (f) High levels of PI(3,5)P2 on endolysosomal membranes promote the recruitment of oligomeric GDP-bound form of SEPT9 which mediates the binding to dynein–dynactin complex.
Figure 2.
Figure 2.
MCSs between endoplasmic reticulum and endolysosomes. The schematic view of different protein complexes involved in the establishment of MCSs between the ER and the endolysosomal compartment (LE/LY). (a) The ER-resident transmembrane protein RNF26 recruits and promotes the ubiquitination of the adaptor protein p62/SQSTM1 which interacts with the membrane-bound endolysosomal protein TOLLIP. These MCSs are reverted by the de-ubiquitinating enzyme USP15. (b) Sortin nexin-19 (SNX19) interacts with PI(3)P-enriched membranes to promote contacts between the ER and LE/LY membranes. (c) The lysosomal transmembrane protein STARD3 establishes interaction with the vesicle-associated ER membrane protein VAP.
Figure 3.
Figure 3.
Nutrients influence lysosome positioning. Under starvation, e.g. in the absence of amino acids and growth factors, mTORC1 signalling is reduced and lysosomes are moved at the cell centre towards MTOC by a dynein–dynactin motor complex. On the contrary, nutrient availability stimulates mTORC1 signalling and promotes peripheral lysosomal localization thanks to the action of kinesin-based motor proteins.
Figure 4.
Figure 4.
Correlation between lysosome positioning and pathological defects. (a) Centripetal/centromeric localization of endolysosomes is often seen in pathological conditions such as lysosomal storage diseases characterized by multiple cellular defects including the centripetal clustering of enlarged lysosomes, defects in the autophagic pathways, mitochondrial activity impairment and lysosomal reformation defects. (b) Peripheral lysosomes are generally referred to as secretory lysosomes which have relevant implications for tumour progression and drug chemoresistance.
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