Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis.
Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis.
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DOI：
10.1016/j.jcmgh.2021.09.017
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发表时间：
2022
影响因子：
7.2
通讯作者：
Gukovskaya AS
中科院分区：
文献类型：
--
作者：
Mareninova OA;Dillon DL;Wightman CJM;Yakubov I;Takahashi T;Gaisano HY;Munson K;Ohmuraya M;Dawson D;Gukovsky I;Gukovskaya AS
自噬体是自噬过程中的中心细胞器，其组装途径包括自噬相关蛋白LC 3/ATG 8的脂化形式LC 3-II介导的经典途径和小G蛋白Rab 9介导的非经典途径。典型的自噬对于胰腺外分泌的稳态是必不可少的，并且其紊乱启动和驱动胰腺炎。非经典自噬的参与尚未探讨。我们研究Rab 9在胰腺自噬和胰腺炎严重程度中的作用。我们使用过表达Rab 9的转基因小鼠（Rab 9 TG）和腺病毒转导腺泡细胞，测量Rab 9对自噬和胰腺炎反应参数的影响。在ATG 5缺陷腺泡细胞中评估典型自噬对Rab 9的影响。在啮齿动物胰腺炎模型和人类疾病中，Rab 9及其膜结合（活性）形式的胰腺水平降低。Rab 9过表达刺激非典型和抑制典型/LC 3介导的自噬体形成的腺泡细胞通过上调ATG 4 B，半胱氨酸蛋白酶，delipidates LC 3-II。相反，ATG 5缺陷导致腺泡细胞Rab 9增加。Rab 9 TG胰腺中典型自噬的抑制与含有线粒体、蛋白质聚集体和trans-Golgi标记物的Rab 9阳性空泡的积累相关。转移到非经典途径引起胰腺炎样损伤的腺泡细胞和加重实验性胰腺炎。结果表明，Rab 9调节胰腺自噬，并表明胰腺炎中经典/LC 3介导的自噬通路和非经典/Rab 9介导的自噬通路之间存在相互拮抗关系。非经典自噬不能替代经典自噬来预防胰腺炎。因此，Rab 9在实验和人类胰腺炎中的减少是维持典型自噬和减轻疾病严重程度的保护性反应。
Autophagosome, the central organelle in autophagy process, can assemble via canonical pathway mediated by LC3-II, the lipidated form of autophagy-related protein LC3/ATG8, or noncanonical pathway mediated by the small GTPase Rab9. Canonical autophagy is essential for exocrine pancreas homeostasis, and its disordering initiates and drives pancreatitis. The involvement of noncanonical autophagy has not been explored. We examine the role of Rab9 in pancreatic autophagy and pancreatitis severity. We measured the effect of Rab9 on parameters of autophagy and pancreatitis responses using transgenic mice overexpressing Rab9 (Rab9TG) and adenoviral transduction of acinar cells. Effect of canonical autophagy on Rab9 was assessed in ATG5-deficient acinar cells. Pancreatic levels of Rab9 and its membrane-bound (active) form decreased in rodent pancreatitis models and in human disease. Rab9 overexpression stimulated noncanonical and inhibited canonical/LC3-mediated autophagosome formation in acinar cells through up-regulation of ATG4B, the cysteine protease that delipidates LC3-II. Conversely, ATG5 deficiency caused Rab9 increase in acinar cells. Inhibition of canonical autophagy in Rab9TG pancreas was associated with accumulation of Rab9-positive vacuoles containing markers of mitochondria, protein aggregates, and trans-Golgi. The shift to the noncanonical pathway caused pancreatitis-like damage in acinar cells and aggravated experimental pancreatitis. The results show that Rab9 regulates pancreatic autophagy and indicate a mutually antagonistic relationship between the canonical/LC3-mediated and noncanonical/Rab9-mediated autophagy pathways in pancreatitis. Noncanonical autophagy fails to substitute for its canonical counterpart in protecting against pancreatitis. Thus, Rab9 decrease in experimental and human pancreatitis is a protective response to sustain canonical autophagy and alleviate disease severity.
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影响因子：
2.5
作者：
Gukovskaya AS;Pandol SJ;Gukovsky I
通讯作者：
Gukovsky I
影响因子：
5.6
作者：
Huang, Chih-Yang;Kuo, Wei-Wen;Huang, Chih-Yang
通讯作者：
Huang, Chih-Yang
影响因子：
6
作者：
Lugea, Aurelia;Waldron, Richard T.;Pandol, Stephen J.
通讯作者：
Pandol, Stephen J.
影响因子：
4.1
作者：
Baron, Rudi A.;Seabra, Miguel C.
通讯作者：
Seabra, Miguel C.
影响因子：
15.9
作者：
Mareninova, Olga A.;Hermann, Kip;Gukovskaya, Anna S.
通讯作者：
Gukovskaya, Anna S.