HMGB1 Encapsulated in Podocyte-Derived Exosomes Plays a Central Role in Glomerular Endothelial Cell Injury in Lupus Nephritis by Regulating TRIM27 Expression

Article

Author: Wang, Xiaorong ; Miao, Xinyan ; Zhang, Wei ; Xing, Lingling ; Tian, Yuexin ; Liu, Yunhe ; Shi, Ke ; Jia, Baiyun ; Zhao, Tongyu ; Liu, Shuxia ; He, Shiwei ; Yuan, Weicheng ; Liu, Jinxi ; Huang, Jie ; Kang, Lihua ; Cui, Huixin ; Feng, Xiaojuan ; Tian, Yu ; Liu, Qingjuan

Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.

01 Mar 2025·Journal of Biological Chemistry

Enhanced kinase translocation reporters for simultaneous real-time measurement of PKA, ERK, and calcium

Article

Author: Dabbs, Austin ; Caterina, Michael J ; Gould, Stephen J ; Gong, Yijing ; Zahra, Fiddia ; Xu, Junhao ; Geske, Aleksander ; Tsai, Shang-Jui

Kinase translocation reporters (KTRs) are powerful tools for single-cell measurement of time-integrated kinase activity but suffer from restricted dynamic range and limited sensitivity, particularly in neurons. To address these limitations, we developed enhanced KTRs (eKTRs) for PKA and extracellular signal-regulated kinase (ERK) by (i) increasing KTR size, which reduces the confounding effect of KTR diffusion through the nuclear pore and (ii) modulating the strength of the bipartite nuclear localization signal in their kinase sensor domains, to ensure that the relative distribution of the KTR between the nucleus and cytoplasmic is determined by active nuclear import, active nuclear export, and relative activity of their cognate kinase. The resultant sets of ePKA-KTRs and eERK-KTRs display high sensitivity, broad dynamic range, and cell type-specific tuning. Moreover, co-expression of optically separable ePKA-KTRs and eERK-KTRs allowed us to simultaneously monitor the activation and inhibition of PKA and ERK, together with calcium levels, in live cells. These eKTRs responded as expected to direct agonists and inhibitors, and also confirmed that crosstalk between the PKA and ERK pathways is highly unbalanced, with the activation of PKA suppressing ERK activity, while activation of ERK induces PKA activity. Taken together, our findings highlight the importance of KTR size and bipartite nuclear localization signal strength to KTR sensitivity and dynamic range, show that different cell types require different eKTRs, and identify ePKA-KTR1.4 and eERK-KTR1.2 as particularly well-suited for monitoring PKA and ERK in primary sensory neurons.

01 Jan 2025·Acta Pharmacologica Sinica

Rab11b promotes M1-like macrophage polarization by restraining autophagic degradation of NLRP3 in alcohol-associated liver disease

Article

Author: Zuo, Long-Quan ; Sun, Ying-Yin ; Jiang, Xin-Yu ; Li, Liang-Yun ; Li, Xiao-Feng ; Yang, Ying-Li ; Zhao, Yu-Xin ; Wang, Hua ; Chen, Xin ; Meng, Xiao-Ming ; Huang, Cheng ; Li, Jun ; Xia, Ran ; Li, Hai-di

Macrophage polarization is vital to mounting a host defense or repairing tissue in various liver diseases. Excessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is related to the orchestration of inflammation and alcohol-associated liver disease (ALD) pathology. Rab GTPases play critical roles in regulating vesicular transport. In this study we investigated the role of Rab11b in ALD, aiming to identify effective therapeutic targets. Here, we first demonstrated a decreased expression of Rab11b in macrophages from ALD mice. Knockdown of Rab11b by macrophage-specific adeno-associated virus can alleviate alcohol induced liver inflammation, injury and steatosis. We found that LPS and alcohol stimulation promoted Rab11b transferring from the nucleus to the cytoplasm in bone marrow-derived macrophages (BMDM) cells. Rab11b specifically activated the NLRP3 inflammasome in BMDMs and RAW264.7 cells to induce M1 macrophage polarization. Rab11b overexpression in BMDMs inhibited autophagic flux, leading to the suppression of LC3B-mediated NLRP3 degradation. We conclude that impaired Rab11b could alleviate alcohol-induced liver injury via autophagy-mediated NLRP3 degradation.

100 Deals associated with Leptomycin B

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Phase 1	-	Pfizer Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2012	Not Applicable	Lung Cancer	-	Doxorubicin	vpofzsfzpx(dyykjozqse) = jhwcuxcxzs qdusrxobig (mrnbundzxh )	-	15 Apr 2012
				Leptomycin B	vpofzsfzpx(dyykjozqse) = csyregjpob qdusrxobig (mrnbundzxh )

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