Lysosomes are core organelles for cellular catabolism and quality control. They are responsible for degrading materials derived from intracellular autophagy, extracellular endocytosis, phagocytosis, and macropinocytosis. In addition to degradation, lysosomes participate in nutrient sensing, mTOR signaling regulation, antigen processing, inflammatory responses, plasma membrane repair, extracellular vesicle release, and regulation of cell death.

Keywords: lysosome; autophagy; endolysosomal system; TFEB; TFE3; mTORC1; LAMP1; LAMP2A; CMA; inflammation; autoimmunity; metabolic diseases

1 Functional Positioning of Lysosomes

1.1 Catabolism and Cellular Homeostasis

Lysosomes contain multiple acidic hydrolases that degrade proteins, lipids, carbohydrates, and nucleic acids. They not only process extracellular materials taken up by cells, but also remove damaged organelles, protein aggregates, and metabolic waste through autophagy. Therefore, lysosomes are important nodes for maintaining cellular homeostasis under nutrient stress, endoplasmic reticulum stress, proteostasis imbalance, and oxidative stress.

1.2 Lysosomes Are Not Merely “Degradation Endpoints”

Traditionally, lysosomes have often been understood as cellular waste-processing structures, but in fact they are also signaling platforms. mTORC1, mTORC2, TFEB, TFE3, AMPK, Rab small GTPases, V-ATPase, and various transporters jointly regulate lysosomal acidification, localization, fusion, regeneration, and metabolic output.

Lysosomal dysfunction does not only cause substrate accumulation. It also affects amino acid recycling, lipid mobilization, antigen presentation, inflammasome activation, immune cell survival, and tissue metabolic adaptation. Therefore, lysosomes are an important intersection between metabolic diseases and autoimmune diseases.

2 The Endolysosomal-Autophagy System

Figure 1. Overview of Lysosome-Associated Membrane Trafficking, Degradation, and Biogenesis Regulation

2.1 Endocytosis, Phagocytosis, and Macropinocytosis

Endocytosis internalizes extracellular materials and plasma membrane receptors into cells, forming early endosomes. Early endosomes can recycle some receptors back to the plasma membrane, or mature into late endosomes and fuse with lysosomes to form endolysosomal structures. This process participates in receptor degradation, nutrient acquisition, and termination of extracellular signaling.

Phagocytosis mainly occurs in immune cells such as macrophages, dendritic cells, and neutrophils. It takes up pathogens, apoptotic cells, or tissue debris through phagosomes. After phagosomes fuse with lysosomes, their contents are degraded by acidic hydrolases and may enter antigen processing and presentation pathways.

Macropinocytosis takes up extracellular fluid and soluble molecules through the formation of larger vesicles and is important in tumor cells, immune cells, and nutrient-stressed cells.

2.2 Macroautophagy, Endosomal Microautophagy, and Chaperone-Mediated Autophagy

Autophagy is the major pathway by which lysosomes degrade intracellular materials. Macroautophagy encloses cytoplasmic materials or organelles within double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. This process depends on the ULK1 complex, Vps34 complex, ATG5-ATG12-ATG16L1 complex, and LC3 lipidation.

Endosomal microautophagy (e-MI) allows cytoplasmic materials to enter the endosomal system and depends on ESCRT-related mechanisms. Chaperone-mediated autophagy (CMA) is more substrate-selective. Proteins containing KFERQ-like motifs can be recognized by HSPA8 and transported into the lysosomal lumen through LAMP2A for degradation.

2.3 Lysosomal Exocytosis and Extracellular Vesicle Release

Lysosomes can move toward the cell periphery and fuse with the plasma membrane, resulting in lysosomal exocytosis. This process participates in plasma membrane repair, local hydrolase release, and extracellular matrix remodeling. Lysosomes can also interact with the multivesicular body system and influence extracellular vesicle release.

In immune and inflammatory environments, lysosomal exocytosis may help cells repair damage, but it may also promote the release of inflammatory mediators, hydrolases, or tissue-destructive components. Therefore, lysosomal secretion has dual significance in autoimmunity and chronic inflammation.

3 Core Regulatory Mechanisms of Lysosomal Function

3.1 Acidification and Hydrolase Activity

The acidic environment inside the lysosomal lumen is mainly maintained by vacuolar-type ATPase (V-ATPase). Low pH provides an appropriate active environment for hydrolases such as cathepsins, lipases, glycosidases, and nucleases. If lysosomal acidification is impaired, degradative capacity may decline even when lysosome number increases.

Lysosomal activity assessment cannot rely only on LAMP1 or LAMP2 expression. Increased LAMP proteins may indicate increased lysosome number, but may also reflect increased lysosomal burden or blocked degradation. More reliable interpretation should combine acidic probes, cathepsin activity, LC3-II, p62/SQSTM1, autophagic flux, and functional readouts.

3.2 TFEB/TFE3 and the CLEAR Network

TFEB and TFE3 are important transcription factors for lysosomal biogenesis and autophagy gene expression. They bind CLEAR elements in target gene promoters and induce the expression of lysosomal membrane proteins, luminal hydrolases, transporters, and ATG genes.

Under nutrient-rich conditions, mTORC1 phosphorylates TFEB/TFE3 and retains them in the cytoplasm. When nutrient deprivation, energy stress, or lysosomal stress occurs, mTORC1 activity decreases, TFEB/TFE3 become dephosphorylated and translocate into the nucleus, enhancing lysosomal and autophagy-related transcriptional programs.

3.3 mTORC1, mTORC2, and Nutrient Sensing

mTORC1 localizes to the cytosolic side of the lysosomal membrane and is a core integrator of amino acid, energy, and growth factor signals. Its activation promotes protein synthesis and cell growth while inhibiting ULK1-mediated autophagy initiation. mTORC2 is also related to lysosome-associated signaling and participates in cell survival, cytoskeleton regulation, and metabolic control.

Thus, the lysosome is a nutrient-sensing platform rather than a simple degradation compartment. When nutrient supply is sufficient, mTORC1 suppresses autophagy. When nutrients are limited or cellular stress increases, autophagy releases amino acids and lipids to provide metabolic compensation.

3.4 Lysosomal Movement and Organelle Interaction

Lysosomes can move along the microtubule system between the perinuclear region and the cell periphery. Perinuclear localization favors fusion with the endoplasmic reticulum, Golgi apparatus, mitochondria, and autophagosomes. Peripheral localization facilitates receptor regulation, exocytosis, plasma membrane repair, and local hydrolase release.

Lysosomes can also form contact sites with mitochondria and participate in mitochondrial fission, calcium signaling, lipid exchange, and metabolic coordination. Abnormal lysosomal localization affects autophagic flux, cell migration, immune cell activation, and tissue injury responses.

4 Lysosomal Damage, Inflammation, and Cell Death

4.1 Lysosomal Membrane Damage and Cathepsin Release

After lysosomal membrane damage, cathepsins can leak into the cytoplasm and trigger lysosome-dependent cell death. Cathepsins can also cleave Bid, linking lysosomal damage with the mitochondrial apoptotic pathway.

Lysosomal membrane damage does not necessarily lead to immediate cell death. Cells can repair the damaged membrane through ESCRT-mediated membrane repair or remove damaged lysosomes through lysophagy. If repair and clearance fail, persistent inflammation and cell death may occur.

4.2 ROS, NLRP3 Inflammasome, and Pyroptosis

Damaged lysosomes can generate or amplify ROS signals and promote NLRP3 inflammasome activation. Activated NLRP3 promotes maturation and release of IL-1β and IL-18 and induces pyroptosis. This process is important in autoimmunity, infection, gout-like inflammation, metabolic inflammation, and kidney injury.

4.3 Lysosomes and Ferroptosis

Lysosomes can affect intracellular labile iron levels through iron storage, iron release, and ferritinophagy. Lysosomal damage, increased ROS, and labile iron accumulation can promote lipid peroxidation and thereby link lysosomes with ferroptosis.

In metabolic diseases, neurodegenerative diseases, and inflammatory injury, the lysosome-iron homeostasis-lipid peroxidation axis may be an important mechanism connecting proteostasis, oxidative stress, and cell death.

5 Lysosomes and Immune Homeostasis

5.1 Antigen Processing and MHC II Presentation

The endolysosomal system participates in MHC class II antigen processing and presentation. Exogenous antigens enter the endosome-lysosome pathway through endocytosis or phagocytosis, are processed by hydrolases, loaded onto MHC II molecules in MHC class II compartments, and ultimately presented to CD4⁺ T cells.

If lysosomal acidification, hydrolase activity, or endosomal maturation is abnormal, antigen processing efficiency may be affected, resulting in insufficient immune activation or abnormal exposure of self-antigens. In autoimmune diseases, abnormal antigen processing, clearance of cell death products, and nucleic acid sensing are often associated with altered lysosomal function.

5.2 Immune Cell Survival and Differentiation

Long-lived immune cells depend on autophagy and lysosomes to maintain mitochondrial quality, proteostasis, and metabolic adaptation. T cells, B cells, macrophages, and dendritic cells all require lysosomal participation during activation, differentiation, and effector function.

Autophagy abnormalities can alter Treg/Th17 balance, affect effector T cell metabolism, weaken the ability of macrophages to clear pathogens, and increase inflammasome activation. These changes can drive persistent autoimmunity and chronic inflammation.

5.3 Autophagy Dysregulation and Inflammatory Amplification

Autophagy clears damaged mitochondria, protein aggregates, and intracellular pathogens, thereby limiting ROS, mtDNA release, and inflammasome activation. If autophagic flux decreases, intracellular damage signals cannot be cleared in time, and inflammatory responses are amplified.

6 Roles of Lysosomes in Metabolic Diseases

6.1 Fatty Liver Disease, NAFLD, and NASH

Hepatocytes rely on autophagy and lipophagy to degrade lipid droplets and release fatty acids. FOXO1 can induce ATG gene expression and promote autophagy-mediated lipid droplet breakdown. Autophagy can also reduce endoplasmic reticulum stress and insulin resistance, exerting a protective role in hepatocellular lipid homeostasis.

In NAFLD and NASH, abnormal lysosomal protein expression, altered autophagic flux, and insufficient lipid droplet clearance may occur. If lipophagy decreases, lipid droplet accumulation, lipotoxicity, inflammation, and fibrosis risk increase. LC3-associated phagocytosis is also considered to potentially participate in protective mechanisms against liver fibrosis.

6.2 Diabetes and Insulin Resistance

In diabetes and insulin resistance, nutrient excess, lipotoxicity, glucotoxicity, AGEs, and oxidative stress can interfere with lysosomal function. Insufficient autophagy aggravates endoplasmic reticulum stress, mitochondrial injury, and inflammatory responses, and affects pancreatic β cell survival and insulin secretion.

In peripheral tissues, the lysosome-autophagy system also affects lipid droplet mobilization, mitochondrial quality control, and insulin signaling sensitivity. Declining lysosomal function may impair the ability of cells to handle nutrient overload and damaged proteins, thereby driving metabolic inflammation.

6.3 Neurodegenerative Diseases

Neurons and other terminally differentiated long-lived cells have high basal autophagy requirements. Insufficient lysosomal activity leads to delayed clearance of protein aggregates, damaged mitochondria, and abnormal lipids, and is associated with Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and other disorders.

Autophagy dysregulation has also been observed in inflammatory nervous system diseases such as EAE and chronic inflammatory demyelinating polyneuropathy. This suggests that lysosomes participate not only in neuronal homeostasis, but also in central immune and inflammatory regulation.

6.4 Lysosomal Storage Diseases

Lysosomal storage diseases are substrate accumulation disorders caused by defects in lysosomal enzymes, transporters, or related membrane proteins. Their pathology arises not only from substrate accumulation, but also involves autophagy blockade, mitochondrial dysfunction, inflammatory activation, and tissue structural damage.

When the kidney, nervous system, or myocardium is involved, lysosomal dysfunction often manifests as protein aggregation, impaired mitophagy, and increased cell death.

7 Roles of Lysosomes in Autoimmune Diseases

7.1 Systemic Lupus Erythematosus

In systemic lupus erythematosus (SLE), abnormalities in autophagy and lysosomal processes can affect immune cell differentiation, clearance of cell death products, and exposure of self-antigens. Treg and Th17 cell imbalance is associated with altered T cell autophagy. Meanwhile, autoantibodies and complement deposition can damage tissue cells, inducing lysosomal stress, ROS generation, and chronic inflammation.

In lupus nephritis, immune complex deposition and complement activation can damage glomerular cells and further affect autophagy-lysosome function in podocytes and renal tubular cells.

7.2 Inflammatory Bowel Disease

In inflammatory bowel disease (IBD), insufficient autophagy-mediated bacterial clearance, abnormal antigen presentation, and enhanced inflammasome activation can all participate in disease progression. Lysosomal functional defects in intestinal epithelial cells and immune cells weaken control of the gut microbiota, promoting dysbiosis and persistent inflammation.

Lysosomal defects in Paneth cells can affect antimicrobial peptide secretion, impairing intestinal barrier and microbial homeostasis. This is an important entry point for lysosomal dysfunction in IBD.

7.3 Sjögren’s Syndrome

In Sjögren’s syndrome, exocrine gland tissues may show altered autophagic activity. Some studies suggest increased autophagic activity in T cell areas of minor salivary glands, while salivary gland epithelial cells show abnormal expression of proteins related to apoptosis, secretion, and lysosomal function.

Lysosome-associated membrane protein LAMP3 has research value in this disease, but it is not exclusive to lysosomes. It can also be found in late endosomes and specific immune activation states. Therefore, in Sjögren’s syndrome research, LAMP3 should be analyzed together with LAMP1, LAMP2, LC3, p62, and functional autophagic flux indicators.

7.4 Multiple Sclerosis and EAE

In multiple sclerosis and its experimental model EAE, autophagy and lysosomal processes can affect central nervous system inflammation, antigen presentation, myelin injury, and immune cell infiltration. Autophagy dysregulation may alter T cell effector function, myelin antigen processing, and inflammatory states of neural glial cells.

8 Product Selection Related to Lysosome Research in Metabolic and Autoimmune Diseases

Lysosomes are key organelles connecting nutrient sensing, proteostasis, immune regulation, and inflammatory responses. Their dysfunction can lead to blocked autophagic flux, abnormal antigen processing, inflammasome activation, lipid metabolic disorder, and tissue injury. Lysosomal changes in metabolic and autoimmune diseases do not follow a single direction and should be comprehensively interpreted according to cell type, disease stage, lysosomal activity, and autophagic flux.

For more related articles, please see below:

[1] PI3K-Akt-mTORC Signaling

[2] Classification and Disease Mechanisms of the Cathepsin Family: Activity Regulation and Research Applications of Cathepsin B, D, K, L, S, and G