# Exosomal cargos modulate autophagy in recipient cells via different signaling pathways

**Authors:** Mehdi Hassanpour, Aysa Rezabakhsh, Jafar Rezaie, Mohammad Nouri, Reza Rahbarghazi

PMC · DOI: 10.1186/s13578-020-00455-7 · 2020-08-01

## TL;DR

This paper explores how exosomes and autophagy interact through shared pathways to maintain cell health and suggests this could lead to new treatments for lysosome-related disorders.

## Contribution

The paper highlights a novel molecular crosstalk between exosome biogenesis and autophagy, emphasizing their shared pathways and mutual modulation.

## Key findings

- Exosomes contain autophagic cargos that can induce autophagy in target cells.
- Exosome biogenesis and autophagy share intertwined molecular pathways and crossbred vesicles called amphisomes.
- The crosstalk between these processes helps maintain cellular homeostasis under stress.

## Abstract

Vesicular system of mammalian cells is composed of two intracellular and extracellular vesicles systems, which contributes to the intra/intercellular communication and cellular homeostasis. These systems mediate transferring of biological molecules like proteins, nucleic acids, and lipids inside the cytoplasm, and between the cells. By the present study, authors describe molecular crosslink between exosome biogenesis and autophagy and take a certain focus on the autophagic cargos of exosomes and signaling pathways involved in exosome-induced autophagy in target cells and vice versa. Autophagy the generation of double-phospholipid vesicles, is a process that engulfs damaged proteins and organelles, share molecular similarity and function synergy with exosomes biogenesis for degradation or exocytosis of certain cargo. Exosomes, the smallest subtype of extracellular vesicles, originating from the membrane of the multivesicular body located inside cells demonstrate key roles in the intracellular and intercellular communication. Growing evidence demonstrates the interaction between exosome biogenesis and autophagy both at intertwined molecular pathways and crossbred vesicles known as amphisomes. Crosstalk between exosome biogenesis and autophagy contributes to maintain cellular homeostasis under external and internal stresses. Moreover, these processes can modulate each other via different signaling pathways. Exosomes contain autophagic cargos that induce autophagy via the cascade of molecular events in target cells, which called here exosome-induced autophagy. Taken together, crosstalk between exosome biogenesis and autophagy plays pivotal roles in cell homeostasis. Shedding light on the interaction between endomembrane systems may promote our knowledge about the relation between exosome and autophagy pathways in lysosome-related disorders against treatments; proposing a theoretical approach for therapy.

## Full-text entities

- **Genes:** Stat5a (signal transducer and activator of transcription 5A) [NCBI Gene 20850] {aka STAT5}, PLD2 (phospholipase D2) [NCBI Gene 5338] {aka PLD1C}, RAB11A (RAB11A, member RAS oncogene family) [NCBI Gene 8766] {aka YL8}, ATM (ATM serine/threonine kinase) [NCBI Gene 472] {aka AT1, ATA, ATC, ATD, ATDC, ATE}, PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3) [NCBI Gene 5289] {aka VPS34, Vps34, hVps34}, Bcl2 (BCL2, apoptosis regulator) [NCBI Gene 24224] {aka Bcl-2}, CD82 (CD82 molecule) [NCBI Gene 3732] {aka 4F9, C33, GR15, IA4, KAI1, R2}, CD81 (CD81 molecule) [NCBI Gene 975] {aka CVID6, S5.7, TAPA1, TSPAN28}, Prkaa2 (protein kinase AMP-activated catalytic subunit alpha 2) [NCBI Gene 78975] {aka Ampk, Ampka2}, Cd63 (CD63 antigen) [NCBI Gene 12512] {aka ME491, Tspan30}, STX8 (syntaxin 8) [NCBI Gene 9482] {aka CARB}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56717] {aka 2610315D21Rik, FRAP, FRAP2, Frap1, RAFT1, RAPT1}, Mir130a (microRNA 130a) [NCBI Gene 387149] {aka Mirn130, Mirn130a, mir-130a}, STX7 (syntaxin 7) [NCBI Gene 8417], ATG3 (autophagy related 3) [NCBI Gene 64422] {aka APG3, APG3-LIKE, APG3L, PC3-96, hApg3}, Eif4ebp1 (eukaryotic translation initiation factor 4E binding protein 1) [NCBI Gene 13685] {aka 4e-bp1, PHAS-I}, ULK1 (unc-51 like autophagy activating kinase 1) [NCBI Gene 8408] {aka ATG1, ATG1A, UNC51, Unc51.1, hATG1}, RPS6KB1 (ribosomal protein S6 kinase B1) [NCBI Gene 6198] {aka PS6K, S6K, S6K-beta-1, S6K1, STK14A, p70 S6KA}, RAB8A (RAB8A, member RAS oncogene family) [NCBI Gene 4218] {aka MEL, RAB8}, Bcl2 (B cell leukemia/lymphoma 2) [NCBI Gene 12043] {aka Bcl-2, C430015F12Rik, D630044D05Rik, D830018M01Rik}, ATG14 (autophagy related 14) [NCBI Gene 22863] {aka ATG14L, BARKOR, KIAA0831}, Vdr (vitamin D (1,25-dihydroxyvitamin D3) receptor) [NCBI Gene 22337] {aka Nr1i1}, Mir19b-2 (microRNA 19b-2) [NCBI Gene 387195] {aka Mirn19b, Mirn19b-2, miR-19b, mir-19b-2}, GIPC1 (GIPC PDZ domain containing family member 1) [NCBI Gene 10755] {aka C19orf3, GIPC, GLUT1CBP, Hs.6454, IIP-1, NIP}, LAP (Laryngeal adductor paralysis) [NCBI Gene 7939], Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, YWHAZ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta) [NCBI Gene 7534] {aka 14-3-3-zeta, HEL-S-3, HEL-S-93, HEL4, KCIP-1, POPCHAS}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Eif2ak2 (eukaryotic translation initiation factor 2-alpha kinase 2) [NCBI Gene 19106] {aka 2310047A08Rik, 4732414G15Rik, Pkr, Prkr, Tik}, MIR486-1 (microRNA 486-1) [NCBI Gene 619554] {aka MIR486, MIRN486, hsa-mir-486, hsa-mir-486-1, mir-486-1}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, EEA1 (early endosome antigen 1) [NCBI Gene 8411] {aka MST105, MSTP105, ZFYVE2}, Tfeb (transcription factor EB) [NCBI Gene 21425] {aka Tcfeb, bHLHe35}, Stat5a (signal transducer and activator of transcription 5A) [NCBI Gene 24918] {aka Stat5}, Bst2 (bone marrow stromal cell antigen 2) [NCBI Gene 69550] {aka 2310015I10Rik, Bst-2, CD317, DAMP-1, GREG}, Atg7 (autophagy related 7) [NCBI Gene 74244] {aka 1810013K23Rik, Agp7, Apg7l, Atg7l, Gm21553}, ANXA2 (annexin A2) [NCBI Gene 302] {aka ANX2, ANX2L4, CAL1H, HEL-S-270, LIP2, LPC2}, PDCD6IP (programmed cell death 6 interacting protein) [NCBI Gene 10015] {aka AIP1, ALIX, DRIP4, HP95, MCPH29}, Tsg101 (tumor susceptibility gene 101) [NCBI Gene 22088] {aka CC2}, Egfr (epidermal growth factor receptor) [NCBI Gene 13649] {aka 9030024J15Rik, Erbb, Errb1, Errp, Wa5, wa-2}, Tppp (tubulin polymerization promoting protein) [NCBI Gene 72948] {aka 2900041A09Rik, TPPP/p25}, Mir30d (microRNA 30d) [NCBI Gene 100314010] {aka rno-mir-30d}, CD63 (CD63 molecule) [NCBI Gene 967] {aka AD1, HOP-26, ME491, MLA1, OMA81H, Pltgp40}, Map1lc3a (microtubule-associated protein 1 light chain 3 alpha) [NCBI Gene 66734] {aka 1010001H21Rik, 4922501H04Rik, LC3, LC3a}, MFN2 (mitofusin 2) [NCBI Gene 9927] {aka CMT2A, CMT2A2, CMT2A2A, CMT2A2B, CPRP1, HMSN6A}, NUP62 (nucleoporin 62) [NCBI Gene 23636] {aka IBSN, SNDI, p62}, Mir758 (microRNA 758) [NCBI Gene 100314176] {aka rno-mir-758}, ATG16L1 (autophagy related 16 like 1) [NCBI Gene 55054] {aka APG16L, ATG16A, ATG16L, IBD10, WDR30}, RAB4A (RAB4A, member RAS oncogene family) [NCBI Gene 5867] {aka HRES-1, HRES-1/RAB4, HRES1, RAB4}, MAP1LC3B (microtubule associated protein 1 light chain 3 beta) [NCBI Gene 81631] {aka ATG8F, LC3B, MAP1A/1BLC3, MAP1LC3B-a}, AGFG1 (ArfGAP with FG repeats 1) [NCBI Gene 3267] {aka HRB, RAB, RIP}, Acta2 (actin alpha 2, smooth muscle, aorta) [NCBI Gene 11475] {aka 0610041G09Rik, Actvs, SMAalpha, SMalphaA, a-SMA, alphaSMA}, H2AX (H2A.X variant histone) [NCBI Gene 3014] {aka H2A.X, H2A/X, H2AFX}, Atg9 (Autophagy-related 9) [NCBI Gene 36821] {aka Atg9a, CG3615, Dmel\CG3615, dAtg9}, CHAF1A (chromatin assembly factor 1 subunit A) [NCBI Gene 10036] {aka CAF-1, CAF1, CAF1B, CAF1P150, P150}, Scamp5 (secretory carrier membrane protein 5) [NCBI Gene 56807] {aka Sc5}, Mir210 (microRNA 210) [NCBI Gene 387206] {aka Mirn210, mir-210, mmu-mir-210}, MAP1LC3A (microtubule associated protein 1 light chain 3 alpha) [NCBI Gene 84557] {aka ATG8E, LC3, LC3A, MAP1ALC3, MAP1BLC3}, Atg13 (autophagy related 13) [NCBI Gene 51897] {aka 1110053A20Rik, D2Ertd391e, Harbi1}
- **Diseases:** ischemic myocardium (MESH:D017682), CML (MESH:D015464), hypoxia (MESH:D000860), myocardial remodeling (MESH:D064752), acute kidney injury (MESH:D058186), DN (MESH:D003928), SNCA (MESH:D000080874), toxicity (MESH:D064420), CVD (MESH:D002318), CMA (MESH:C564093), injury (MESH:D014947), myocardial infarction (MESH:D009203), atherosclerosis (MESH:D050197), inflammation (MESH:D007249), gastric cancer (MESH:D013274), oral squamous cancer (MESH:D018307), tumorigenesis (MESH:D063646), pancreatic cancer (MESH:D010190), epilepsy (MESH:D004827), I/R injury (MESH:D015427), spinal cord injury (MESH:D013119), fibrotic livers (MESH:D017093), Parkinson's disease (MESH:D010300), airway fibrosis (MESH:D005355), necrosis (MESH:D009336), Tumor (MESH:D009369), GAIP (MESH:C563663), NSCLC (MESH:D002289), DNA damage (MESH:D004266), breast cancer (MESH:D001943), HRS (MESH:C566928), liver fibrosis (MESH:D008103), lysosomal diseases (MESH:D016464)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Microsporidium sp. VB (species) [taxon 2561062], Mycobacterium tuberculosis (species) [taxon 1773], Drosophila melanogaster (fruit fly, species) [taxon 7227], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], HCV [taxon 11103]
- **Mutations:** rs3910105
- **Cell lines:** HST-T6 — Saguinus labiatus (Red-chested mustached tamarin), Transformed cell line (CVCL_JG25), K562 — Homo sapiens (Human), Blast phase chronic myelogenous leukemia, BCR-ABL1 positive, Cancer cell line (CVCL_0004), HSC-T6 — Rattus norvegicus (Rat), Transformed cell line (CVCL_0315), H9C2 — Rattus norvegicus (Rat), Spontaneously immortalized cell line (CVCL_0286)

## Figures

4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC7395405/full.md

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Source: https://tomesphere.com/paper/PMC7395405