Lysosomes As a Therapeutic Target

REVIEWS Lysosomes as a therapeutic target Srinivasa Reddy Bonam 1,2, Fengjuan Wang1,2 and Sylviane Muller 1,2,3,4* Abstract | Lysosomes are membrane- bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases — including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease — this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs. Endocytosis Discovered in the 1950s by Christian de Duve, lyso Nevertheless, with recent advances in understand A vesicle- mediated process by somes are membrane bound vesicles containing ing of lysosomal function and dysfunction in dis which cells engulf membrane numerous hydrolytic enzymes that can break down eases, promising novel opportunities for therapeutic and extracellular materials. biological polymers such as proteins, lipids, nucleic intervention through targeting lysosomes specifically Several endocytic pathways — 1,2 phagocytosis, pinocytosis and acids and polysaccharides . Lysosomes have long are beginning to emerge. This Review will provide a receptor- mediated endocytosis been known to have a key role in the degradation brief overview of lysosomal biogenesis, structure and — utilize different mechanisms and recycling of extracellular material via endocytosis and function, and describe the role of lysosomal dysfunc to internalize material. Clathrin- phagocytosis, and intracellular material via autophagy tion in LSDs as well as other, more common diseases. mediated endocytosis is the (reviewed elsewhere2–5) (Fig. 1). The products of lyso Specifically, the article will focus on organ specific and major endocytic pathway in mammalian cells. somal degradation through these processes can be non organspecific autoimmune diseases, including trafficked to the Golgi apparatus for reuse or for release lupus, rheumatoid arthritis (RA) and multiple sclerosis from the cell through lysosomal exocytosis, which is (MS), as these have not been extensively reviewed important in immune system processes. In addition, elsewhere, but will also briefly highlight neurodegen it has become clear more recently that lysosomes erative disorders such as Alzheimer disease (AD) and 1CNRS–University of have an important role in other cellular processes Parkinson disease (PD), to further illustrate the breadth Strasbourg, Biotechnology including nutrient sensing and the control of energy and nature of the emerging therapeutic opportunities. and Cell Signalling, Illkirch, metabolism3,5–7 (Fig. 1). The current ‘toolbox’ of pharmacological agents that France. Alterations in lysosomal functions, either in the modulate lysosomal functions and emerging novel tar 2 Laboratory of Excellence fusion processes involved in the general pathways gets and strategies in this set of indications will be high Medalis, Team Neuroimmunology and mentioned above or related to the function of lyso lighted. It should be noted that therapeutic approaches Peptide Therapy, Institut de somal enzymes and non enzymatic proteins, can result to treat inflammatory and autoimmune diseases aim to Science et d’Ingénierie in broad detrimental effects, including failure to clear inhibit the deleterious excessive lysosomal activity, Supramoléculaire (ISIS), potentially toxic cellular waste, inflammation, apopto whereas lysosomal activation would be the goal in the Strasbourg, France. sis and dysregulation of cellular signalling8. Such defects treatment of neurodegenerative diseases. Although 3 University of Strasbourg have been implicated in many diseases, ranging from beyond the scope of this review, such approaches may Institute for Advanced Study, lysosomal storage disorders Strasbourg, France. rare (LSDs), which are caused have applications in other diseases in which lysosomes 4Fédération Hospitalo- by the dysfunction of particular lysosomal proteins, to may play a role, including cancer, metabolic diseases and 15,16 Universitaire OMICARE, more common autoimmune and neurodegenerative dis ageing (reviewed elsewhere ). Fédération de Médecine orders5,9,10. Despite some limitations, impressive results Translationnelle de have been achieved in treating several LSDs through Lysosomal biogenesis, structure and function Strasbourg, Strasbourg enzyme replacement therapy (ERT). In addition, sub The formation of mature lysosomes is a complex process, University, Strasbourg, France. stantial efforts have been focused on therapeutically which involves the fusion of late endosomes that contain *e- mail: sylviane.muller@ targeting the autophagy processes upstream of lyso material taken up at the cell surface with transport ves 11–14 5,8,17 unistra.fr somes . However, there has so far been less attention icles that bud from the trans Golgi network . These https://doi.org/10.1038/ on investigating the potential to directly target lysosomes vesicles contain nearly 60 different hydrolytic enzymes s41573-019-0036-1 with small molecules and peptide drugs. (grouped into nucleases, proteases, phosphatases, lipases, NATURE REVIEWS | DRUG DISCOVERY VOLUME 18 | DECEMBER 2019 | 923 REVIEWS a Phagocytosis Exocytosis An endocytic process by which certain cells called phagocytes Phagocytosis Nucleus (for example, macrophages) PM repair, bone resorption, immune internalize large particles response and pathogenic content discharge Endocytosis (>0.5 µm) such as bacteria, Early endosome other microorganisms, foreign particles or aged red blood cells, for example, to form a Early Nutrient sensing phagosome. endosome mTORC1 inactive mTORC1 active Endosome Lysosome • Low energy levels • High amino acid levels Autophagy • High pH • Low pH Pinocytosis A vital, finely- regulated and • Ion channel regulation • Ion channel regulation evolutionarily- conserved intracellular pathway that Autophagy continuously degrades, recycles and clears unnecessary or dysfunctional b Autophagy cellular components. HSPA8 PLIN2/3 Autophagy is crucial for cell P adaptation to the environment AMPK and to maintain cell homeostasis, especially under stress conditions. LD Golgi apparatus Microautophagy Cytosolic apparatus, meant for the regulation of proteins Macroautophagy (modification, storing and Lysosome transportation) and some Lytic enzymes forms of lipids to the other cytosolic compartments via the P LAMP2A trans-Golgi network or outside Glycosylation site the cell. Lysosome Lysosomal exocytosis Lys-HSPA8 A process of the secretory lumen pathway in which lysosomes Glial ﬁbrillary Lys-HSP90 MTORC2 are fused with the plasma acidic protein membrane and empty their Lys-HSPA8 EF1a Rac1 contents outside the cell. This P PHLPP process plays an important AKT Cytoplasmic role in plasma membrane L CMA F K tail repair, bone resorption, KFERQ-HSPA8 C V H immune response and TFEB M H H elimination of pathogenic CLEAR A KFERQ motif N– stores (mainly in lysosomal G Y storage disorders). Cytosol E Nucleus Q F Lysosomal storage Substrate HSPA8 C– disorders (LSDs). A group of CMA heterogeneous disorders caused by defects in the Fig. 1 | The central position of lysosomes at the crossroads of major autophagic pathways. a | Functional lysosomes lysosomal enzymes leading are involved in the degradation (endocytic and autophagic) and regulation of exogenous and endogenous cellular to the accumulation of material, including recycling processes. Extracellular material endocytosed by the endosomes and intracellular cargo unmodified or unprocessed internalized by the autophagosomes fuse with lysosomes for degradation, which produces energy (ATP production) and components in the lysosomes, source molecules for the macromolecules. Mechanistic target of rapamycin complex 1 (mTORC1) plays a key role in which ultimately influence lysosomal nutrient sensing signals (lysosome-to-nucleus axis) to regulate energy metabolism. Factors such as energy other vital pathways in the levels, type of pH, ion channel regulation and others decide the fate of the catabolic process. During lysosomal exocytosis, cells. LSDs implicate various vital systems of the human the lysosomal content favours plasma membrane (PM) repair, bone resorption, immune response and elimination of body including the skeleton, pathogenic stores. b | The lysosome is the ultimate cell compartment that digests unwanted protein materials generated brain, skin, heart and central by macroautophagy , microautophagy (pathways during which the cytoplasmic material is trapped in the lysosome by a nervous system, which are process of membrane invagination) and chaperone- mediated autophagy (CMA). In general, lipid droplets (LDs) are connected with different degraded by lipophagy , a subtype of macroautophagy , which is activated by cytosolic lipases. CMA has also been metabolic pathways. demonstrated to participate in the degradation of LDs in which perilipin (PLIN2/3) proteins are phosphorylated (P) by AMP- activated protein kinase (AMPK) with the help of the HSPA8 chaperone. Mechanistic target of rapamycin complex

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