Mechanism of cargo sorting into small extracellular vesicles

Figures & data

Table 1. List of cargos of sEVs sorting mechanisms

Type ofcargo	Sorted cargo	Related molecules	Sorting mechanism		Role of exosomes/Related disease/miRNA Binding Motifs	Extraction Methods for sEVs	Ref.
protein	Nedd4 familyproteins	Ndfip1	ubiquitination-like	Ndfip1 interacts with Nedd4 family proteins	Remove the harmful substances to improve neuronal survival in case of brain injury.	1	[20, 30]
	α-synuclein	SUMO		SUMOylation of proteins via interacting with phosphoinositols and some subunits of ESCRT complex such as ALIX, VPS4.	Helpful for analyzing the Parkinson’s Disease pathogenesis at molecular level.	1 and 2	[25,26]
	RasG12V	UBL3		UBL modify proteins through the C-terminal cysteine residue disulfide bond.	Sorting of RasG12V could improve the activation of Ras signaling.	1	[27]
	eGFP	pX, Alix	ESCRT subunits	C-terminal of Px interacts with V domain of Alix to sort the eGFPpX into exosomes.	Promotes secretion of virions and foreign proteins through exosomes.	1	[33]
	AQP2	LIP5, Vps4		LIP5 binds with AQP2, and CHMP1B recruit LIP5 to MVBs, which then fuse with plasma membrane to release as exosomes.	Transfer specific membrane proteins so as to respond to cellular and environmental signals.	/	[36]
	β-catenin	Vps4A, CHMP4B		Vps4A may facilitate the sorting of β-catenin into exosomes through the interaction with β-catenin and CHMP4B.	Prevent epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma by dampening β-catenin signing	1 and 5	[37]
	Stomatin flottlin-1	lipid rafts	lipid and tetraspanins	Lipoproteins associated with lipid raft components	Emphasizing the existence of lipidmicrodomains in exosomal membranes and the direct impact of exosomes in regulatory mechanisms	1 and 2	[40,41]
	LMP1	CD63		Copurification of CD63 for its completed location patterns	LMP1-modified exosomes show the ability to enhance progression of EBV-associated cancers.	1 and 2	[46]
	CD10	CD9		CD9 interacts with CD10 via establishing the chimeras	Release of CD10 peptidase activity with exosomes may effectively regulate extracellular matrix microenvironments	1	[48]
RNA	miR-198, miR-601	hnRNPA2B1	RNA Binding Proteins	SUMOylation of hnRNPA2B1 bind with GGAG of some miRNAs.	GGAG motif	1 and 2	[61]
	miR-3470a, miR-194	SYNCRIP		RBPs bind with motifs of specific miRNAs	GGCU motif	1	[65]
	miR-233, miR-133	YBX-1			CAUC motif	1 and 2 and 3	[66,67,69]
	miR-193	MVP			NA	1 and 2	[71]
	miR-155	FMR1			AAUGC motif	1	[77]
	miR-10b, let-7a	Ago2		Ago2 bind with miRNA to form an Ago2-miRNA complex	NA	1 and 2	[79–86]
	miR-10b, miR-100	KRAS,	KRAS status and nSMase2 influence the profile and the level of miRNA.		Change of miRNA expression may play therapeutic roles in reversing the tumorigenic effects on account of the aberrant miRNA expression.	1	[86]
	miR-210 miR-10b	nSMase2	Release of exosomes and exosomal miRNA are regulated by nSMase2.				[84, 85]
	mRNA	CTGCC core domain, miRNA-binding site	Zipcode-like 25 nucleotide sequence which contain CTGCC core domain and miRNA-binding site work as a Zipcode exist in the 3’UTR of mRNA to promote the sorting.		Can be a potential approach for cancer gene therapy by incorporating sequences into 3’UTR of therapeutic RNAs.	1	[89]
		YB-1	RNA Binding Proteins	YB-1 recognize and bind to eRNA-specific motifs with different affinity, and this connection is assisted by the C-terminal of YB-1.	(1) ACCAGCCU (2) UAAUCCCA (3) CAGUGAGC	1	[90]
DNA	gDNA	Micronuclei (MN), Tetraspanins	CD63 surrounded gDNA released by disrupted MN, and participate in the exosome biogenesis and finally be sorted into exosomes.		Highlights the function of nEXO in cancer biomarker development.	1 and 4	[94]

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