GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain.
GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain.
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DOI：
10.1038/s41467-021-27056-3
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发表时间：
2021-11-18
影响因子：
16.6
通讯作者：
Wood MJA
中科院分区：
文献类型：
--
作者：
Dar GH;Mendes CC;Kuan WL;Speciale AA;Conceição M;Görgens A;Uliyakina I;Lobo MJ;Lim WF;El Andaloussi S;Mäger I;Roberts TC;Barker RA;Goberdhan DCI;Wilson C;Wood MJA
细胞外囊泡（EV）是生物纳米颗粒，在细胞间通讯中发挥重要作用，并具有作为药物输送载体的潜力。在这里，我们展示了糖酵解酶甘油醛-3-磷酸脱氢酶 (GAPDH) 在 EV 组装和分泌中的作用。我们观察到高水平的 GAPDH 通过磷脂酰丝氨酸结合基序 (G58) 与 EV 外表面结合，从而促进广泛的 EV 聚类。果蝇 EV 生物发生模型的进一步研究表明，GAPDH 是内体区室中管腔内囊泡正常生成所必需的，并促进囊泡聚集。 GAPDH 衍生的 G58 肽与 dsRNA 结合基序的融合能够将小干扰 RNA (siRNA) 高效加载到 EV 表面。在全身注射后，此类囊泡可有效地将 siRNA 递送至亨廷顿病小鼠模型的大脑多个解剖区域，从而导致大脑不同区域的亨廷顿基因沉默。 GAPDH 通常被认为是一种管家基因，在糖酵解中发挥作用。在这里，作者表明 GAPDH 具有促进内体中囊泡聚集的作用，并且可以将 siRNA 加载到细胞外囊泡的表面，从而可用于治疗。
Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain. GAPDH is generally considered a housekeeping gene and functions in glycolysis. Here, the authors show that GAPDH has a role in promoting vesicle clustering in endosomes and can load siRNA onto the surface of extracellular vesicles, which can be exploited therapeutically.
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影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
4.8
作者：
Fillebeen, C;Descamps, L;Pierce, A
通讯作者：
Pierce, A
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
DOI：
10.1083/jcb.201401072
发表时间：
2014-09-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Corrigan L;Redhai S;Leiblich A;Fan SJ;Perera SM;Patel R;Gandy C;Wainwright SM;Morris JF;Hamdy F;Goberdhan DC;Wilson C
通讯作者：
Wilson C
影响因子：
7.7
作者：
Edgar, James R.;Manna, Paul T.;Robinson, Margaret S.
通讯作者：
Robinson, Margaret S.