RIP3 impedes transcription factor EB to suppress autophagic degradation in septic acute kidney injury.
RIP3 impedes transcription factor EB to suppress autophagic degradation in septic acute kidney injury.
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RIP3 阻碍转录因子 EB，从而抑制脓毒症急性肾损伤中的自噬降解。
DOI：
10.1038/s41419-021-03865-8
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发表时间：
2021-06-08
影响因子：
9
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Li R;Zhao X;Zhang S;Dong W;Zhang L;Chen Y;Li Z;Yang H;Huang Y;Xie Z;Wang W;Li C;Ye Z;Dong Z;Liang X
自噬是脓毒性急性肾损伤（阿基）中重要的肾脏保护机制。受体相互作用蛋白激酶3（RIP 3）与脓毒性阿基期间的肾小管损伤和肾功能障碍有关。在这里，我们研究了RIP 3在脓毒症阿基中对自噬的作用和机制。我们发现，在脂多糖（LPS）诱导的脓毒症阿基小鼠和LPS处理的培养肾近端肾小管上皮细胞（PTECs）的肾脏中，RIP 3活化，伴随着自噬体标记物LC 3 II和自噬底物p62的积累。溶酶体抑制剂没有进一步增加LPS处理的PTECs中LCII或p62的水平。此外，抑制RIP 3减弱了体内和体外LPS处理下LC 3 II和p62的异常积累。通过在体内利用mCherry-GFP-LC 3自噬报告基因小鼠和在体外过表达mRFP-GFP-LC 3的PTECs，我们观察到RIP 3的抑制恢复了自溶体的形成，并消除了LPS处理下积累的自噬体。这些结果表明，RIP 3损害自噬降解，有助于自噬体的积累。从机制上讲，转录因子EB（TFEB）的核转位，溶酶体和自噬途径的主调节剂，在LPS诱导的小鼠和LPS处理的PTECs中受到抑制。RIP 3的抑制在体内和体外恢复了TFEB的核转位。免疫共沉淀进一步显示LPS处理的PTECs中RIP 3和TFEB的相互作用。此外，LAMP 1和组织蛋白酶B的表达，两个潜在的靶基因的TFE B参与溶酶体功能，在体内和体外的LPS处理下减少，这种减少被拯救通过抑制RIP 3。最后，TFEB的过表达恢复了LPS处理的PTECs中的自噬降解。总之，本研究已经确定了RIP 3在脓毒症阿基中通过阻碍TFEB-溶酶体途径抑制自噬降解的关键作用，为预防和治疗脓毒症阿基提供了潜在的治疗靶点。
Autophagy is an important renal-protective mechanism in septic acute kidney injury (AKI). Receptor interacting protein kinase 3 (RIP3) has been implicated in the renal tubular injury and renal dysfunction during septic AKI. Here we investigated the role and mechanism of RIP3 on autophagy in septic AKI. We showed an activation of RIP3, accompanied by an accumulation of the autophagosome marker LC3II and the autophagic substrate p62, in the kidneys of lipopolysaccharide (LPS)-induced septic AKI mice and LPS-treated cultured renal proximal tubular epithelial cells (PTECs). The lysosome inhibitor did not further increase the levels of LCII or p62 in LPS-treated PTECs. Moreover, inhibition of RIP3 attenuated the aberrant accumulation of LC3II and p62 under LPS treatment in vivo and in vitro. By utilizing mCherry-GFP-LC3 autophagy reporter mice in vivo and PTECs overexpression mRFP-GFP-LC3 in vitro, we observed that inhibition of RIP3 restored the formation of autolysosomes and eliminated the accumulated autophagosomes under LPS treatment. These results indicated that RIP3 impaired autophagic degradation, contributing to the accumulation of autophagosomes. Mechanistically, the nuclear translocation of transcription factor EB (TFEB), a master regulator of the lysosome and autophagy pathway, was inhibited in LPS-induced mice and LPS-treated PTECs. Inhibition of RIP3 restored the nuclear translocation of TFEB in vivo and in vitro. Co-immunoprecipitation further showed an interaction of RIP3 and TFEB in LPS-treated PTECs. Also, the expression of LAMP1 and cathepsin B, two potential target genes of TFEB involved in lysosome function, were decreased under LPS treatment in vivo and in vitro, and this decrease was rescued by inhibiting RIP3. Finally, overexpression of TFEB restored the autophagic degradation in LPS-treated PTECs. Together, the present study has identified a pivotal role of RIP3 in suppressing autophagic degradation through impeding the TFEB-lysosome pathway in septic AKI, providing potential therapeutic targets for the prevention and treatment of septic AKI.
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影响因子：
16
作者：
Mandal P;Berger SB;Pillay S;Moriwaki K;Huang C;Guo H;Lich JD;Finger J;Kasparcova V;Votta B;Ouellette M;King BW;Wisnoski D;Lakdawala AS;DeMartino MP;Casillas LN;Haile PA;Sehon CA;Marquis RW;Upton J;Daley-Bauer LP;Roback L;Ramia N;Dovey CM;Carette JE;Chan FK;Bertin J;Gough PJ;Mocarski ES;Kaiser WJ
通讯作者：
Kaiser WJ
自噬限制内毒素急性肾损伤，并改变肾小管上皮细胞因子表达。
影响因子：
3.7
作者：
Leventhal JS;Ni J;Osmond M;Lee K;Gusella GL;Salem F;Ross MJ
通讯作者：
Ross MJ
RGMb 通过 MLKL 依赖性机制抑制肾小管细胞坏死性凋亡，从而预防急性肾损伤
DOI：
10.1073/pnas.1716959115
发表时间：
2018-02-13
影响因子：
11.1
作者：
Liu, Wenjing;Chen, Binbin;Xia, Yin
通讯作者：
Xia, Yin
影响因子：
4.8
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
通讯作者：
Mocarski, Edward S.
影响因子：
2.4
作者：
Coupienne, Isabelle;Fettweis, Gregory;Piette, Jacques
通讯作者：
Piette, Jacques