USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1
USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1
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DOI：
10.1038/s41418-021-00907-8
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发表时间：
2021-11-27
影响因子：
12.4
通讯作者：
Liu, Wei
中科院分区：
文献类型：
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作者：
Rong, Yuluo;Fan, Jin;Liu, Wei
脊髓缺血再灌注损伤（SCIRI）是一种严重的创伤，可导致感觉和运动功能的丧失。铁凋亡是一种新的调节性细胞死亡形式，其特征在于铁依赖性脂质过氧化物积累。铁凋亡在各种疾病中已被研究，然而，SCIRI中铁凋亡的确切功能和分子机制仍不清楚。在这项研究中，我们证明，铁凋亡是参与SCIRI的病理机制。抑制铁凋亡可促进SCIRI后小鼠运动功能的恢复。此外，我们发现，泛素特异性蛋白酶11（USP 11）在缺氧-复氧后的神经元细胞和I/R损伤小鼠脊髓中显著上调。体外敲除USP 11和体内敲除USP 11（-/Y）可显著降低神经元细胞的铁凋亡。在小鼠中，这促进了SCIRI后的功能恢复。相反，在体外，USP 11过表达导致经典的铁凋亡事件。小鼠中USP 11的过表达导致SCIRI后铁凋亡增加和功能恢复不良。有趣的是，上调USP 11的表达似乎也增加了自噬体的产生，并导致大量的自噬通量，这是USP 11可能增强铁凋亡的潜在机制。自噬的减少明显减弱了USP 11介导的铁凋亡，自噬诱导与USP 11具有协同作用。重要的是，USP 11通过稳定Beclin 1促进自噬激活，从而导致铁凋亡。总之，这项研究表明，铁凋亡与SCIRI密切相关，USP 11在调节铁凋亡中起着关键作用，并将USP 11介导的自噬依赖性铁凋亡作为治疗SCIRI的有希望的靶点。
Spinal cord ischemia-reperfusion injury (SCIRI) is a serious trauma that can lead to loss of sensory and motor function. Ferroptosis is a new form of regulatory cell death characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis has been studied in various diseases; however, the exact function and molecular mechanism of ferroptosis in SCIRI remain unknown. In this study, we demonstrated that ferroptosis is involved in the pathological mechanism of SCIRI. Inhibition of ferroptosis could promote the recovery of motor function in mice after SCIRI. In addition, we found that ubiquitin-specific protease 11 (USP11) was significantly upregulated in neuronal cells after hypoxia-reoxygenation and in the spinal cord in mice with I/R injury. Knockdown of USP11 in vitro and KO of USP11 in vivo (USP11(-/Y)) significantly decreased neuronal cell ferroptosis. In mice, this promotes functional recovery after SCIRI. In contrast, in vitro, USP11 overexpression leads to classic ferroptosis events. Overexpression of USP11 in mice resulted in increased ferroptosis and poor functional recovery after SCIRI. Interestingly, upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux, a potential mechanism through which USP11 may enhance ferroptosis. The decreased autophagy markedly weakened the ferroptosis mediated by USP11 and autophagy induction had a synergistic effect with USP11. Importantly, USP11 promotes autophagy activation by stabilizing Beclin 1, thereby leading to ferroptosis. In conclusion, this study shows that ferroptosis is closely associated with SCIRI, and that USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of SCIRI.