A fine-tuning mechanism underlying self-control for autophagy: deSUMOylation of BECN1 by SENP3
A fine-tuning mechanism underlying self-control for autophagy: deSUMOylation of BECN1 by SENP3
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自噬自我控制的微调机制：SENP3 对 BECN1 的去SUMOylation
DOI：
10.1080/15548627.2019.1647944
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发表时间：
2019-08-04
期刊：
影响因子：
13.3
通讯作者：
Yi, Jing
中科院分区：
文献类型：
--
作者：
Liu, Kejia;Guo, Chu;Yi, Jing
sumo酰化及其相关酶在自噬调控中的作用尚不清楚。基于我们之前的研究发现sumo2 /3特异性肽酶SENP3是一种氧化应激反应分子，我们研究了SUMOylation与巨噬/自噬之间的关系。我们发现，与Senp3（+/+）小鼠相比，在基础和禁食条件下，Senp3（+/+）小鼠的肝脏自噬增加。我们构建了肝脏特异性senp3敲除小鼠；这些缺乏senp3的肝组织也表现出自噬增加。在肝脏和其他细胞系中，在SENP3基因被敲低后，在细胞以血清和氨基酸剥夺的形式遭受饥饿之前和之后，自噬通量都加快了。我们证明BECN1/beclin 1， BECN1- pik3c3复合物的核心分子，可以被PIAS3主要在K380位点偶联sumo3，并被SENP3去苏修饰。BECN1的基础SUMOylation在细胞饥饿时增加，通过促进BECN1与其他复杂组分UVRAG、PIK3C3和ATG14的相互作用，增强自噬体的形成，从而促进PIK3C3的活性。相反，SENP3去氧化BECN1，破坏BECN1-PIK3C3复合物的形成或稳定性，从而抑制PIK3C3活性。在基础条件下，尤其是在饥饿条件下，当SENP3因活性氧的增加而积累时，BECN1的去ummoylation抑制了自噬的诱导。因此，可逆SUMOylation调节自噬的程度，而SENP3为微调自噬诱导提供了内在的溢流阀。
The roles of SUMOylation and the related enzymes in autophagic regulation are unclear. Based on our previous studies that identified the SUMO2/3-specific peptidase SENP3 as an oxidative stress-responsive molecule, we investigated the correlation between SUMOylation and macroautophagy/autophagy. We found that Senp3(+/-) mice showed increased autophagy in the liver under basal and fasting conditions, compared to Senp3(+/+) mice. We constructed a liver-specific senp3 knockout mouse; these Senp3-deficient liver tissues showed increased autophagy as well. Autophagic flux was accelerated in hepatic and other cell lines following knockdown of SENP3, both before and after the cells underwent starvation in the form of the serum and amino acid deprivation. We demonstrated that BECN1/beclin 1, the core molecule of the BECN1-PIK3C3 complex, could be SUMO3-conjugated by PIAS3 predominantly at K380 and deSUMOylated by SENP3. The basal SUMOylation of BECN1 was increased upon cellular starvation, which enhanced autophagosome formation by facilitating BECN1 interaction with other complex components UVRAG, PIK3C3 and ATG14, thus promoting PIK3C3 activity. In contrast, SENP3 deSUMOylated BECN1, which impaired BECN1-PIK3C3 complex formation or stability to suppress the PIK3C3 activity. DeSUMOylation of BECN1 restrained autophagy induction under basal conditions and especially upon starvation when SENP3 had accumulated in response to the increased generation of reactive oxygen species. Thus, while reversible SUMOylation regulated the degree of autophagy, SENP3 provided an intrinsic overflow valve for fine-tuning autophagy induction.