European Review for Medical and Pharmacological Sciences 2021; 25: 1641-1649 The important role of TFEB in -lysosomal pathway and autophagy-related diseases: a systematic review

T.-T. SONG1, R.-S. CAI1, R. HU2, Y.-S. XU1, B.-N. QI3, Y.-A. XIONG1

1School of Pharmacy, Zunyi Medical University, Xinpu District, Zunyi, Guizhou, China 2Chongqing Pharmaceutical Technology Evaluation and Certification Center, Chongqing, China 3Department of Public Health, Shanxi University of Chinese Medicine, Xianyang, China

Tingting Song, Rongshan Cai and Rong Hu are co-first authors

1 Abstract. – Autophagy is a main metabol- one-mediated autophagy (CMA) . Macroautoph- ic process in which eukaryotic cells use lyso- agy is the most common autophagy phenomenon, somes to eliminate abnormal and dam- also known as the autophagy-lysosomal pathway aged organelles to maintain cell homeostasis. (ALP), which mainly degrades abnormal pro- Studies have revealed that neurodegenerative teins and damaged organelles and regulates many diseases, tumor, hepatic diseases, etc. are relat- physiological and pathological processes. Under ed to abnormal autophagy processes in recent years. Recent studies have shown that TFEB is nutrient-rich conditions, autophagy remains at a a major transcription regulator of autophagy-ly- basal level and mainly acts as a housekeeper re- sosomal pathway (ALP) transcriptional regula- sponsible for degrading long-lived proteins and tion, which positively regulates the expression recycling damaged organelles. In conditions of of autophagy and lysosomal biogenesis-related starvation, autophagy is activated to provide en- , thereby promoting autophagosome for- ergy supply to maintain cell survival2. Deficits in mation, autophagosome- fusion, and the ALP lead to aggregation, the gener- degradation of autophagy substrates. It has al- so been found that TFEB promotes clearance of ation of toxic protein species and accumulation intracellular substrates through lysosomal exo- of dysfunctional organelles, which are hallmarks cytosis. Therefore, the study of biological func- of lysosomal storage disease, neurodegenerative tions and related regulatory mechanisms of diseases, nephrotic cystinosis, etc. Thus, correct- TFEB will provide important clues and theoreti- ing ALP defects and enhancing the activity of the cal basis for further explaining its physiological pathway are potential therapeutic strategies3. As pathogenesis and the treatment of related dis- eases. a major regulator of the ALP, TFEB is a potential target for the treatment of various autophagy-re- Key Words: lated diseases. TFEB, Regulator, Autophagy, Lysosome, Autopha- The EB (TFEB) is a mem- gosome, Pathway. ber of the MiTF/TFE (microphthalmia-transcrip- tion factor E) family of transcription factors of the leucine zipper bHLH-LZ (basic-helix-loop-helix Introduction leucine-zipper), which can bind to the promoter motif of autophagy genes to induce autophago- Autophagy is an evolutionarily conserved deg- some formation, autophagosome-lysosome fu- radation pathway through which cells can adapt sion, and degradation of autophagy substrates4. to nutrient starvation, oxidative stress, lysosomal Studies have shown that TFEB is not only in- dysfunction as well as others. According to the volved in autophagy but also lysosomal biogene- delivery differences of cytoplasmic cargo to the sis and exocytosis. The have shown a lysosome, autophagy is typically categorized into central role in cellular degradation and recycling macroautophagy, microautophagy, and chaper- processes, and its correct function is required to

Corresponding Authors: Yongai Xiong, MD; e-mail: [email protected] Yingshu Xu, MD; e-mail: [email protected] Baoning Qi, MD; e-mail: [email protected] 1641 T.-T. Song, R.-S. Cai, R. Hu, Y.-S. Xu, B.-N. Qi, Y.-A. Xiong maintain cell homeostasis. The lysosomal genes protein molecules, which mainly affect the phos- network is called CLEAR (coordinated lysosomal phorylation of TFEB specific serine. The mam- expression and regulation)5. TFEB can recognize malian target of rapamycin complex 1 (mTORC1) E-box and M-box sequences of the CLEAR net- is the best regulator of mammalian autophagy, work, activate downstream genes and promote and its interaction with TFEB is regulated by their transcription, resulting in an increased num- the lysosomal nutrient-sensing (LYNUS) ma- ber of lysosomes and higher levels of lysosomal chinery. Under normal conditions (such as low enzymes, thereby enhancing lysosomal catabolic lysosomal pH or high nutrients), the V-ATPase activity. It was also found that TFEB can cause complex activates the small Rag GTPase (Rags), calcium flow into cells by activating calcium a component of the LYNUS machinery, which channel protein MCOLN1, which promotes the recruits mTORC1 to the lysosomal membrane. fusion of lysosome and plasma membrane. Over- Then, mTORC1 directly phosphorylates TFEB at expression of TFEB in lysosomal storage diseases Ser142 and Ser211 sites and inactivate it. YWHA/ can promote the removal of metabolic wastes6. chaperone proteins 14-3-3 also bind to phosphor- ylated TFEB to prevent its nuclear translocation, The Mechanism of TFEB Regulation indirectly regulating autophagy7. However, in the It is currently believed that the main signaling context of external stimuli (such as starvation or pathways that regulate the occurrence of autoph- oxidative stress), the amino acid content in the agy include mTOR pathway and mTOR-indepen- lysosomal lumen decreases, resulting in the in- dent pathway, the latter including AMPK, PI3K, activation of Rags. Accordingly, mTORC1 disso- TNFR, etc. signaling pathways. Among them, the ciates from the lysosomal membrane and cannot mTOR signaling pathway is known to be the main phosphorylate TFEB, then TFEB travels to the way to negatively regulate autophagy. TFEB is a nucleus and activates its transcriptional program key transcription molecule regulating autophagy to adapt to cellular catabolic demands. The Rags at the transcriptional level and it can promote the constitutive active form remains TFEB in the cy- expression of multiple lysosomal genes, thereby toplasm, which is independent of the nutrient sta- regulating the production and efflux function of tus of the cell8. autolysosomes. Medina et al9 found that lysosomal calcium in TFEB transcriptional activity and nuclear HeLa cells is released into the cytoplasm through translocation are related to the TFEB phosphor- calcium channel MCOLN1/TRPML1 upon nutri- ylation status. mTOR is a more important kinase ent deprivation, which can activate the phospha- known to phosphorylate TFEB, which can in- tase calcineurin, thereby promoting the dephos- activate TFEB and localize it in the cytoplasm. phorylation of TFEB and inducing it to translocate mTOR inhibitor can cause TFEB dephosphory- into the nucleus, activating transcriptional target late and incorporate it into the nucleus, thereby genes. However, the consumption of MCOLN1 exerting its transcriptional activity. After TFEB inhibits the release of lysosomal calcium and enters the nucleus, there are two ways to regu- the activation of calcineurin, thereby preventing late autophagy. One is to activate the expression TFEB dephosphorylation during starvation. Up- of various autophagy-related molecules (e.g., Ag on chemically induced ER stress, TFEB nuclear molecules, LC3) through transcription to enhance translocation can also be promoted. Activation cell autophagy so that the damaged organelles are of TFEB through ER stress required a protein degraded by autophagosomes and autolysosomes, kinase RNA-like endoplasmic reticulum kinase which can recycle the degradation products (such (PERK, also known as EIF2AK3)-dependent as amino acids) for cells. The other is to combine mechanism, which can activate calcineurin to the E-box element of CLEAR to transcriptionally dephosphorylate TFEB10. Currently, it is known activate the expression of lysosomal pathway-re- that TFEB is activated mainly by inhibiting the lated molecules, especially the expression of lyso- activity of mTORC1. For example, mTORC1 in- somal-associated membrane protein LAMP1, to hibitor-Torin1 can induce TFEB nuclear translo- promote lysosome formation in vitro (Figure 1). cation, which is an important negative regulatory mechanism. However, mTORC1 is also involved Mammalian Target of Rapamycin in the regulation of cell growth and metabolism Complex 1 and has a wide range of biological functions. In TFEB subcellular localization and its tran- the long run, inhibition of mTORC1 may bring scriptional activity are strictly regulated by many unpredictable side effects. Therefore, activation

1642 Role of TFEB in autophagy-lysosomal pathway and autophagy-related diseases

Figure 1. The regulation of TFEB activity. of TFEB by the mTOR non-inhibitory pathway have demonstrated that mTOR-independent auto- may be less deleterious to cells. phagy activator activates TFEB by in- hibiting AKT activity and increases TFEB nucle- Extracellular Signal-Regulated Kinase 2 ar accumulation12. For example, when trehalose Extracellular signal regulated kinase 2 (ERK2), is given to a mouse model of Batten’s disease, it which is a member of the mitogen-activated protein can promote the clearance of cellular protein ag- kinase 1 (MAPK1), can phosphorylate TFEB at gregates, reduce neuropathology and prolong the serine 142 site and regulate its subcellular localiza- survival time of diseased mice, suggesting the tion. ERK2 phosphorylates TFEB and sequester it broad applicability of this method. These findings in the cytoplasm in the presence of sufficient cellu- collectively open up a new idea for the removal lar nutrients. In starvation conditions, ERK2 does of cellular protein aggregates in TFEB-mediated not interact with TFEB, resulting in TFEB dephos- neurodegenerative storage diseases. phorylates and enters into the nucleus to promote Protein kinase C (PKC) is a crucial controller the expression of autophagy-related genes11. of activating TFEB by mTOR-independent path- way. PKC has many subtypes, including alpha, Protein Kinase beta, delta, and other subtypes. It is reported13 that (AKT) phosphorylates TFEB PKC can activate the transcription factor TFEB at Ser467 by the mTOR-independent mechanism while inactivating the transcriptional repressor to inhibit TFEB nuclear translocation. Studies ZKSCAN3 through two parallel signal cascades.

1643 T.-T. Song, R.-S. Cai, R. Hu, Y.-S. Xu, B.-N. Qi, Y.-A. Xiong

Table I. Regulatory proteins and modes of action of TFEB. No Regulatory proteins Modes of action

1 mTOR Phosphorylation 2 Rag GTPases Phosphorylation 3 MAPK Phosphorylation 4 P38 Phosphorylation 5 GSK3β Phosphorylation 6 Erk 1/2 Phosphorylation 7 Calcineurin Dephosphorylation 8 AMPK Dephosphorylation 9 PKCβ Dephosphorylation 10 STUB1 Dephosphorylation 11 Protein phosphatase 2A(PP2A) Dephosphorylation 12 PIAS3 SUMO 13 Acetyltransferase GCN5 Acetylation 14 Suberoylanilide hydroxamic acid (SAHA) Acetylation

The ingenol analogue HEP14 activates PKCα and teoclasts. Stimulated by the osteoclast differenti- PKCδ, which can inactivate glycogen synthase ation factor RANKL, PKCβ phosphorylates the kinase-3β (GSK3β) by phosphorylation, resulting serine region at the C-terminus of TFEB, which in the reduced phosphorylation of GSK3β on the promotes the expression of lysosomal biogenesis, serine 134 and 138 sites of TFEB, thereby pro- and increases the resorption function of differen- moting TFEB activation and its nuclear trans- tiated osteoclasts. location. In addition, PKCδ can activate JNK2 (c-Jun N-terminal kinase 2) and p38 MAPK (p38 AMP-Activated Protein Kinase mitogen-activated protein kinase), which can Under nutrient-rich conditions, the stability of phosphorylate transcription inhibitors ZKSCAN3 co-activator-associated arginine methyltransfer- (zinc finger protein with KRAB and SCAN3 do- ase 1 (CARM1) is regulated by the SKP2-con- mains) at Thr153, and results in its inactivation taining E3 ubiquitin ligase in the nucleus. Un- and sequesters it in the cytoplasm, relieving the der the condition of nutrient deficiency (co-ac- inhibitory effect of ZKSCAN3 on lysosomal syn- tivator-associated arginine methyltransferase 1) thesis. PKC activators can promote the clearance CARM1-dependent histone arginine methylation of cellular protein aggregates and lipid droplets. plays an important role in the process of autoph- Therefore, they are viable in the treatment of ly- agy. Adenylate-activated protein kinase (AMPK) sosomal-related diseases. In osteoclasts, TFEB can increase the protein levels of CARM1 and the is activated by another mechanism. Studies have dimethylation of histone H3 Arg17, which is me- shown that14 selective deletion of TFEB can re- diated by the AMPK-SKP2-CARM1 signal axis. duce the resorption of bone matrix in mouse os- CARM1 acts as a transcriptional co-activator by

Table II. Downstream regulatory factors and functions of TFEB. No Downstream regulator factors Functions

1 The coordinated lysosomal expression Promoting the expression of lysosomal genes. and regulation (CLEAR) network, E-box and M-box sequences 2 Lysosomal genes network: ARSA, ARSB, Increasing lysosomal population ATP6V0E1, ATP6V1H, CLCN7, CTSA, CTSB, CTSD, CTSF, GALNS, GBA, GLA, GNS, HEXA, LAMP1, MCOLN1, MAGLU, NEU1, PASP, SCPEP1, SGSH, TMEM55B, TPP1

3 Acid hydrolases, lysosomal acidification machinery, Raising the levels of lysosomal enzymes membrane proteins and promoting degradation of lysosomal substrates

1644 Role of TFEB in autophagy-lysosomal pathway and autophagy-related diseases forming a complex with TFEB15. Increasing ev- cannot be degraded normally and accumulate in idence has demonstrated that AMPK deficiency the lysosome, causing tissue or organ dysfunc- leads to a partial reduction of SKP2-mediated nu- tion. The lysosome is a central component of cel- clear CARM1, which causes cardiac autophagy lular catabolism. Most processes based on lyso- dysfunction in the elderly. somes – including macromolecular degradation, autophagy, lysosomal exocytosis, etc. – are regu- Small Ubiquitin-Like Modifier SUMO lated by TFEB transcription. Pompe disease21 is a The small ubiquitin-like modifier SUMO can lysosomal storage disorder in which glycogen ac- also modify TFEB. Miller et al16 found that PIAS3 cumulates abnormally in muscle, whereby AAV can induce SUMO-1 to modify TFEB at Lys316 (adeno-associated virus)-mediated TFEB deliv- in COS-7 cells (monkey kidney fibroblasts). In- ery can induce exocytosis of lysosomes, which is deed, it has been recently reported that17 SUMO beneficial to remove excess glycogen. This over- modification of TFEB can promote the expression expression also improves overall autophagy and of genes related to autophagy and lysosomal bio- lysosomal function. Fraldi et al22 performed in synthesis, inducing autophagy and lysosome for- autophagy-deficient muscles also indicate that the mation in macrophages, thereby hydrolyzing lip- clearance of accumulative substances requires a ids in macrophages to cholesterol and promoting functional autophagy degradation pathway. its efflux, and ultimately inhibiting the formation of macrophage foam cells. Neurodegenerative Storage Diseases Increasing evidence focuses on the autopha- Curcumin Analog C1 gy-lysosomal pathway because its activity reg- Zhang et al18 have shown that curcumin is ulation is closely related to the pathogenesis of non-toxic and has a wide spectrum of pharma- neurodegenerative diseases. Arotcarena et al23 cological activities, which can inhibit the PI3K- have shown that lysosomal biogenesis and func- AKT-mTOR signaling pathway to enhance auto- tion have provided a suitable target for manipu- phagy. However, curcumin has poor water solu- lating lysosomal degradative pathways. TFEB bility and low oral bioavailability, restricting its participates in the intracellular clearance process clinical development. Curcumin analog C1 has mainly by enhancing lysosomal biosynthesis, cel- been considered as a new orally effective activa- lular exocytosis, the expression of degradative tor of TFEB, which can specifically bind to the enzymes, and lysosomal proteostasis to act as a N-terminal glycine and alanine-rich region of cellular clearance regulator. In rodent models of TFEB in an mTOR-independent manner, thereby neurodegenerative diseases (including Alzhei- promoting TFEB nuclear translocation, and it is mer’s disease, Parkinson’s disease, and Hunting- possibly achieved by reducing the interaction of ton’s disease), heterologous expression of TFEB is TFEB and YWHA/14-3-319. This finding has an beneficial to improve the disease phenotype and important implication for the treatment of many promote lysosomal clearance. autophagy-related diseases. The main pathological features of Alzhei- The upstream and downstream regulatory fac- mer ’s Disease (AD) are neurofibrillary tangles tors related to TFEB signaling pathway are shown (NFT) formed by extracellular β-amyloid (Aβ) in Table I and Table II. plaque deposition and intracellular Tau pro- tein hyperphosphorylation (p-Tau). Xiao et al24 TFEB as a Therapeutic Target for Diseases have shown that ALP can regulate the metabo- We observed human and animal models, sug- lism of Aβ. Acting as a major activator of ALP, gesting20 that impaired TFEB signaling pathways TFEB-mediated beneficial effects have been can contribute to a variety of diseases. Indeed, the confirmed in Aβ and Tau pathology in multiple regulation of TFEB activity has become an effec- AD mouse models. Polito et al25 found that in the tive means in the development of related diseases. rTg4510 mouse model of Tau lesions, TFEB deliv- ery can effectively reduce neurofibrillary tangles Lysosomal Storage Disease and improve neurodegenerative behavior. Fur- Lysosomal storage disease (LSD) is a group of thermore, TFEB overexpression can selectively hereditary metabolic diseases whose pathogene- target p-Tau protein, but does not exert harmful sis is that genetic mutations lead to defects of re- effects on normal Tau protein. lated acid hydrolases or accessory proteins in the Parkinson’s disease (PD) is a common neu- lysosome; as a result, the metabolites in the body rodegenerative disease. The typical pathologi-

1645 T.-T. Song, R.-S. Cai, R. Hu, Y.-S. Xu, B.-N. Qi, Y.-A. Xiong cal feature is the selective deletion of substantia mitochondrial bioenergy, indicating that increas- nigra-striatum dopaminergic neurons and the ing TFEB levels can protect alcoholic fatty liver discovery of Lewy bodies formed by abnormally caused by ethanol. Quercetin can also reverse the folded α-synuclein aggregation in the remaining inhibitory effect of ethanol on the nuclear translo- neurons. The overall animal and isolated cell re- cation of TFEB and show a similar effect to Torin search26 support that aggregated α-synuclein can 1, which can promote the nuclear translocation of affect the transcriptional activity of TFEB, caus- TFEB and improve the autophagy-lysosomal dys- ing damage to the autophagy-lysosomal degrada- function caused by ethanol29. tion pathway. However, using drugs or transgenic technology to increase the activity of TFEB can Spinobulbar Muscular Atrophy restore lysosomal biosynthesis and improves dis- The pathological features of spinobulbar ease phenotype. For example, AAV-mediated de- muscular atrophy (SBMA) are due to the repeat livery of TFEB in the brain of a PD rat model ob- morbid expansion of the trinucleotide (CAG) se- tained by overexpressing α-synuclein can reduce quences in the genes encoding the androgen re- the accumulation of α-synuclein and improve ceptor (AR) protein, which ultimately leads to neurodegenerative behavior deficits. polyQ-AR formation. In the spinal cord of SBMA Huntington’s disease (HD) is a neurodegener- mice30, it was found that polyQ-AR reduced the ative disease. Due to the abnormal expansions of expression of TFEB by chelating nuclear factor the CAG trinucleotide sequence in the coding re- YA (NF-YA), thereby reducing ALP activity and gion of the Huntington (HTT) , the HTT pro- enhancing polyQ-AR toxicity. Treating SBMA tein misfolds into a pathogenic conformation, ac- mice with paeoniflorin can promote the nuclear celerating the degeneration of neurons. Based on translocation of TFEB and the expression of the the HD mouse model study, Tsunemi et al27 found ubiquitin-protease complex system by increas- that the expression of TFEB and its downstream ing the expression of nuclear factor-YA (NF-YA), genes were significantly decreased. Through per- thereby promoting the clearance of polyQ-AR oxisome proliferator-activated receptor γ co-acti- and improving the disease phenotype. Cortes et vator 1α (PGC-1α) overexpression corrected the al31 also found that both AR and polyQ-AR can defects of TFEB, thereby promoting the degrada- directly interact with TFEB, but AR is a TFEB tion pathway of autophagolysosome. Eventually, co-activator that promotes its transcriptional ac- the accumulated HTT protein in the mice was tivity, while polyQ-AR reduces the activity of reduced. In addition, experiments conducted by TFEB in SBMA motor neurons and neuron pre- TFEB silencing and PGC1α overexpression, as cursor cells from patients, resulting in decreased well as TFEB overexpression and PGC1α silenc- expression of TFEB target genes and defects in ing, demonstrated that PGC1α acts upstream of autophagy flux. The above research results indi- TFEB, thus, targeting the PGC1α-TFEB axis is cate that polyQ-AR causes tissue-specific dysreg- highly attractive for the treatment of this disease. ulation of TFEB and suggest that it can be treated by enhancing autophagy. Hepatic Disease Accumulating evidence shows that autophagy Nephropathic Cystinosis plays an important role in maintaining the homeo- Nephropathic cystinosis is caused by muta- stasis of the liver. Autophagy is involved in the tion of the CTNS biallelic genes, resulting in the process of recycling cellular nutrients and quality lack of cystine ​lysosomal transporter-cystinosin, control of subcellular organelles. Defects in auto- which is a proton-cystine symporter responsible phagy and lysosomal function can lead to various for the excretion of cystine and protons from the liver pathologies. TFEB regulates lysosomal bio- lysosomal lumen, and the accumulation of cystine synthesis. Chao et al28 found that the levels of total into lysosomes, consequently causing proximal TFEB and nuclear TFEB in the ethanol-induced tubular dysfunction (such as Fanconi syndrome), mouse liver injury model were lower than in the which eventually develops into end-stage renal normal group, and the biosynthetic capacity of ly- disease. Rega et al32 have shown that32 the lack sosomes was reduced. However, Torin-1 (mTOR of cystinosin can reduce the total expression of activity inhibitor) or adenovirus vector-mediated TFEB. Andrzejewska et al33 detected that the overexpression of TFEB can increase TFEB levels mTOR signaling pathway in cystinotic cells has in liver tissue, reduce ethanol damage to liver and changed. The lack of cystinosin inhibits the mTOR steatosis, and increase lysosomal biosynthesis and signaling pathway, as well as the lysosomal stress

1646 Role of TFEB in autophagy-lysosomal pathway and autophagy-related diseases response caused by cystine accumulation, which thereby affecting the process of dendritic cells can lead to TFEB compensatory nuclear translo- and T cells binding through the MHC pathway to cation, but it is still insufficient. Overexpression present exogenous antigens, ultimately affecting of TFEB can promote lysosomal exocytosis and the immune response37. lower the levels of cystine, which brings new hope for the treatment of nephropathic cystinosis. Tumor In the process of tumorigenesis, autophagy has Atherosclerosis a dual role. When cells are stimulated by envi- In the development of atherosclerosis (AS), ronmental factors, they can remove toxic proteins macrophages phagocytose excess cholesterol and damaged organelles through the autophagy derived from extracellular or obtained from the pathway to inhibit cell carcinogenesis; but once conversion of oxidized low-density lipoprotein in tumors form, autophagy can provide nutrients for lysosomes, which causes macrophage lysosomal cancer cells and contribute to the development dysfunction, and the vascular wall locally produc- of a tumor. Cancer cells have a higher energy re- es an inflammatory response, thereby promoting quirement than normal cells to support accelerat- the formation of macrophage foam cells and AS ed cell growth38. When nutrient supply is limited, plaques34. Thus, enhancing lysosomal function cancer cells can mobilize energy by scavenging and promoting cholesterol efflux from macro- nutrients through autophagy-lysosomal pathways. phages are effective means to treat atherosclero- Gomes et al39 have shown that excessive lyso- sis. Related research has shown35 that TFEB is a somal activity is a characteristic of cancer recur- major regulator of lysosomal biogenesis, which rence. TFEB can control the transcription process increases lysosomal lipids catabolism and oxi- of autophagy and lysosomal biogenesis and has dation pathways while inhibits the biosynthesis become an important regulator of tumor energy of it. TFEB can hydrolyze lipids into cholester- metabolism. For example, in renal cell carcino- ol through PGC-1α-PPARα signaling pathway, ma (RCC), chromosomal translocation involving whereby ABCA1-mediated cholesterol efflux TFEB, increased expression, and easy transloca- from cells to reduce lipid load. Simultaneously, tion into the nucleus can initiate the transcription it can reduce the secretion of pro-inflammatory of downstream genes and promote the formation (interleukin-1β) and inhibit excessive of autophagolysosomes40. Calcagnì et al41 treat- activation of inflammatory bodies, improving the ment with Wnt signaling pathway inhibitors sig- progression of AS. nificantly inhibited tumor growth, indicating that targeting Wnt signaling may be used for the treat- Immune Response ment of TFEB-associated RCC. Overexpression The main feature of the immune response is to of TFEB can activate the Wnt pathway, induce the use the inflammatory reaction to eliminate patho- occurrence of kidney cancer and the proliferation gens and other foreign bodies, thereby helping and invasion of cancer cells. Therefore, blocking tissue regeneration and repair. The disorder of the downstream pathway of TFEB activation can inflammatory response can cause a variety of dis- provide an important target for the production of eases. Brady et al36 have shown that the ALP plays anticancer agents. an anti-inflammatory role in the inflammatory response, mainly through its negative feedback regulation of the inflammatory body and indirect- Conclusions ly reduces . As the main regulator of autophagy and lysosomal function, TFEB can TFEB is an important transcription factor in link autophagy and lysosomal dysfunction with the cell and occupies an important position in the inflammatory diseases. The autophagolysosome process of lysosome and cell autophagy. In this system plays a key role in the immune response review, we have highlighted the role of TFEB in by regulating various aspects of antigens presen- the successful completion of autophagy and auto- tation. TFEB can regulate the immune function phagy-related diseases. TFEB is just like a mas- by inducing the activation of lysosomes. After ter switch of the autophagy-lysosome pathway. TFEB is activated, it can inhibit the expression Blocking the transcriptional activity of TFEB will of exogenous antigens mediated by (major histo- affect the production and clearance of lysosome. compatibility complex) MHCI, and at the same Thus, the regulatory mechanism of TFEB and its time enhance antigens presentation of MHCII, role in autophagy-related diseases are worthy of

1647 T.-T. Song, R.-S. Cai, R. Hu, Y.-S. Xu, B.-N. Qi, Y.-A. Xiong study, which can provide a theoretical basis for 11) Li T, Wang S, Yang C, Wu H, Li Z, Liu H, Liu W. the treatment of diseases caused by ALP dysfunc- TFEB regulation--a new idea for the treatment of kidney diseases. Chinese Journal of Pathophysi- tion and the development of new drugs. ology 2018; 34: 754-759. 12) Palmieri M, Pal R, Nelvagal HR, Lotfi P, Stinnett GR, Seymour ML, Chaudhury A, Bajaj L, Bondar Funding VV, Bremner L, Saleem U, Tse DY, Sanagasetti D, This work was supported by the Guizhou Provincial Re- Wu SM, Neilson JR, Pereira FA, Pautler RG, Rod- search Foundation for Basic Research, China (Grant No. ney GG, Cooper JD, Sardiello M. mTORC1-inde- Qiankehejichu [2018]1426), Union Foundation of Zunyi Sci- pendent TFEB activation via Akt inhibition pro- ence and Technology Board, and Zunyi Medical University motes cellular clearance in neurodegenerative (Grant No. Zunshikehe Shezi [2017]19). storage diseases. 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