KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a

Song, Lin; Tang, Shi; Han, Xiaolei; Jiang, Ziying; Dong, Lingling; Liu, Cuicui; Liang, Xiaoyan; Dong, Jixin; Qiu, Chengxuan; Wang, Yongxiang; Du, Yifeng

doi:10.1038/s41467-019-09720-x

Cited by 169 publications

(139 citation statements)

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“…Firstly, we identified that exosome secretion increased significantly via IRF-1/Rab27a in TECs as the initial adaptive response to albumin overload, and KIBRA might participated in stabilizing of Rab27a as reported before 29 . Previous studies have suggested that stress conditions, such as hypoxia, proteinuria increased exosomes release from renal TECs 14,20 , while the underlying mechanisms remain unclear.…”

Section: Discussionsupporting

confidence: 53%

“…5f). Considering that KIBRA has been proven as an adaptor-like protein to prevent Rab27a from ubiquitination for degradation in kidney 29 , KIBRA siRNA was transfected in TECs to investigate the role of KIBRA in Rab27a expression. Knockdown of KIBRA attenuated upregulation of Rab27a protein in TECs exposed to albumin ( Supplementary Fig.…”

Section: Interferon Regulatory Factor 1 (Irf-1) Is Induced As the Tramentioning

confidence: 99%

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Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease

et al. 2020

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Exosomes are increasingly recognized as vehicles of intercellular communication. However, the role of exosome in maintaining cellular homeostasis under stress conditions remained unclear. Here we show that Rab27a expression was upregulated exclusively in tubular epithelial cells (TECs) during proteinuria nephropathy established by adriamycin (ADR) injection and 5/6 nephrectomy as well as in chronic kidney disease patients, leading to the increased secretion of exosomes carrying albumin. The active exosome production promoted tubule injury and inflammation in neighboring and the producing cells. Interferon regulatory factor 1 (IRF-1) was found as the transcription factor contributed to the upregulation of Rab27a. Albumin could be detected in exosome fraction and co-localized with exosome marker CD63 indicating the secretion of albumin into extracellular space by exosomes. Interestingly, inhibition of exosome release accelerated albumin degradation which reversed tubule injury with albumin overload, while lysosome suppression augmented exosome secretion and tubule inflammation. Our findings revealed that IRF-1/Rab27a mediated exosome secretion constituted a coordinated approach to lysosome degradation for albumin handling, which lead to the augment of albumin toxicity as a maladaptive response to maintain cell homeostasis. The findings may suggest a novel therapeutic strategy for proteinuric kidney disease by targeting exosome secretion.

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Section: Discussionsupporting

confidence: 53%

Section: Interferon Regulatory Factor 1 (Irf-1) Is Induced As the Tramentioning

confidence: 99%

Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease

et al. 2020

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“…Since their original description over 30 years ago, exosomes are now known as a subtype of extracellular vesicles (EVs) with the size range 50–150 nm and can be harvested from cell culture or isolated from patient's body fluids which can be subsequently modified in vitro and transferred back to the same patient . Exosomes are released from cells upon fusion of multivesicular body with the plasma membrane, different from microvesicles, which are formed and released by budding from the plasma membrane of cells . Apart from exosomes and microvesicles, the nomenclature of EVs also includes microparticles, ectosomes, oncosomes, and apoptotic bodies .…”

Section: Introductionmentioning

confidence: 99%

Exosomes and Nanoengineering: A Match Made for Precision Therapeutics

et al. 2019

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Intense efforts from both scientists and physicians across Australia have been devoted onward advancing studies to fill the gap in understanding the biology and pathogenesis underlying cancer development. Exosomes are membrane-bound bio-nanoparticles secreted or released by most cells into the extracellular space. There has been an increasing interest in such bio-nanoparticles over the past 10 years, evident from the publication number of only 324 papers in 2006 to a massive increase to 4603 publications in 2018 with the search term "exosome" based on title/abstract in PubMed. Among these studies, 151 articles published from 2007 to 2018 are from Australian institutions, with 33 papers published in 2018. Such a strong surge of interest is due to discoveries that exosomes play key roles in intercellular and intertissue communication mediated by virtue of cargos contained inside the membrane-confined space. Furthermore, exosome cargos, including proteins, mRNAs and miRNAs, are linked to the Targeted exosomal delivery systems for precision nanomedicine attract wide interest across areas of molecular cell biology, pharmaceutical sciences, and nanoengineering. Exosomes are naturally derived 50-150 nm nanovesicles that play important roles in cell-to-cell and/or cell-to-tissue communications and cross-species communication. Exosomes are also a promising class of novel drug delivery vehicles owing to their ability to shield their payload from chemical and enzymatic degradations as well as to evade recognition by and subsequent removal by the immune system. Combined with a new class of affinity ligands known as aptamers or chemical antibodies, molecularly targeted exosomes are poised to become the next generation of smartly engineered nanovesicles for precision medicine. Here, recent advances in targeted exosomal delivery systems engineered by aptamer for future strategies to promote human health using this class of human-derived nanovesicles are summarized.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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“…23 Our recent study showed that kidney and brain protein (KIBRA), an adaptor-like protein, can regulate the secretion of exosomes through a Rab27A-dependent mechanism, and participate in the progression of AD pathology. 24,25 Another of our recent studies indicated that the up-regulation of mammalian target of rapamycin (mTOR) facilitates the release of tau into the extracellular space in an exosome-independent manner in SH-SY5Y cells. 26 More recently, research has shown that the mTOR complex 1 (mTORC1) also regulates the release of exosomes through a Rab27A-dependent mechanism.…”

Section: Exosomesmentioning

confidence: 99%

<p>Targetting Exosomes as a New Biomarker and Therapeutic Approach for Alzheimer’s Disease</p>

Yin

et al. 2020

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Alzheimer's disease (AD) is a neurodegenerative disease that mainly occurs in old age and involves progressive cognitive impairment. AD has become a major global issue for public health, with approximately 24 million people currently affected by the disease. Estimates indicted that this number will quadruple by 2050. Because of the high incidence of AD, there is an urgent need to develop new strategies to diagnose and treat AD. Many recent studies have indicated the multiple, yet somewhat controversial, roles of exosomes in AD. Although the underlying mechanisms by which exosomes play a role in AD are still unknown, current evidence suggests that exosomes can carry and spread toxic amyloid-beta, and hyperphosphorylated tau, between cells, and then induce apoptosis, thus contributing to the loss of neurons. In addition, exosomes appear to possess the ability to reduce brain amyloid-beta, and tau hyperphosphorylation, and transfer neuroprotective substances between neural cells. The accumulating data brings hope that the application of exosomes may be helpful for early diagnostics and the identification of new therapeutic targets for AD. Here, we summarized the various roles of exosomes, and how they might relate to the pathogenesis of AD. We also highlight the potential application of exosomes as a therapeutic option in AD therapy.

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KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a

Cited by 169 publications

References 50 publications

Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease

Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease

Exosomes and Nanoengineering: A Match Made for Precision Therapeutics

<p>Targetting Exosomes as a New Biomarker and Therapeutic Approach for Alzheimer’s Disease</p>

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