ANXA6 suppresses the tumorigenesis of cervical cancer through autophagy induction.
ANXA6 suppresses the tumorigenesis of cervical cancer through autophagy induction.
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ANXA6 通过自噬诱导抑制宫颈癌的肿瘤发生。
DOI：
10.1002/ctm2.208
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发表时间：
2020-10
影响因子：
10.6
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Sun X;Shu Y;Xu M;Jiang J;Wang L;Wang J;Huang D;Zhang J
自噬是真核生物中保守的细胞内降解途径。ANXA 6（annexin A6）属于钙依赖性膜和磷脂结合蛋白家族。在这里，我们将ANXA 6确定为饥饿诱导的自噬中新合成的蛋白质，并将其验证为调节自噬体形成的新型自噬调节剂。 ANXA 6敲除可减弱饥饿诱导的自噬，而其表达的恢复可增强自噬。ANXA 6靶点的GO（基因本体论）分析显示，ANXA 6与许多RAB GTP酶相互作用，靶向内吞和吞噬途径，表明ANXA 6通过蛋白质运输发挥其功能。ATG9A（autophagy-related 9A）是唯一的多跨膜蛋白，其通过再循环内体的运输是自噬体形成的重要步骤。我们的结果表明，ANXA 6能够通过RAB蛋白或F ‐ actin将适当的ATG9A+囊泡从内体运输到自噬体。此外，ANXA 6表达的恢复通过抑制PI3K（磷酸肌醇3激酶）-AKT和ERK（细胞外信号调节激酶）信号通路（自噬的负调节因子）抑制mTOR（雷帕霉素的哺乳动物靶蛋白）活性。在功能上，ANXA 6表达与宫颈癌中的LC 3（微管相关蛋白1轻链3）表达相关，ANXA 6通过自噬诱导抑制肿瘤发生。我们的研究结果揭示了ANXA 6在肿瘤抑制和自噬调节中的重要机制。自噬是真核生物中保守的细胞内降解途径。ANXA 6（膜联蛋白A6）属于钙依赖性膜和磷脂结合蛋白家族。在这里，我们将ANXA 6确定为饥饿诱导的自噬中新合成的蛋白质，并将其验证为调节自噬体形成的新型自噬调节剂。ANXA 6敲低减弱饥饿诱导的自噬，其表达的恢复增强自噬。对ANXA 6靶标的GO（基因本体论）分析显示，ANXA 6与许多RAB GTP酶相互作用，并靶向内吞和吞噬途径，表明ANXA 6通过蛋白质运输发挥其功能。ATG9A（autophagy related 9A）是唯一的多跨膜蛋白，其通过再循环内体的运输是自噬体形成的重要步骤。我们的结果表明，在饥饿条件下，ANXA 6能够通过RAB蛋白或F ‐ actin将适当的ATG9A从内体运输到自噬体。此外，ANXA 6表达的恢复通过抑制PI3K（磷酸肌醇3激酶）-AKT和ERK（细胞外信号调节激酶）信号通路（自噬的负调节因子）抑制mTOR（雷帕霉素的哺乳动物靶蛋白）活性。在功能上，ANXA 6表达与宫颈癌中的LC 3（微管相关蛋白1轻链3）表达相关，ANXA 6通过自噬诱导抑制肿瘤发生。我们的研究结果揭示了ANXA 6在肿瘤抑制和自噬调节中的重要机制。
Autophagy is an intracellular degradation pathway conserved in eukaryotes. ANXA6 (annexin A6) belongs to a family of calcium‐dependent membrane and phospholipid‐binding proteins. Here, we identify ANXA6 as a newly synthesized protein in starvation‐induced autophagy and validate it as a novel autophagy modulator that regulates autophagosome formation. ANXA6 knockdown attenuates starvation‐induced autophagy, while restoration of its expression enhances autophagy. GO (gene ontology) analysis of ANXA6 targets showed that ANXA6 interacts with many RAB GTPases and targets endocytosis and phagocytosis pathways, indicating that ANXA6 exerts its function through protein trafficking. ATG9A (autophagy‐related 9A) is the sole multispanning transmembrane protein and its trafficking through recycling endosomes is an essential step for autophagosome formation. Our results showed that ANXA6 enables appropriate ATG9A+ vesicle trafficking from endosomes to autophagosomes through RAB proteins or F‐actin. In addition, restoration of ANXA6 expression suppresses mTOR (mammalian target of rapamycin) activity through the inhibition of the PI3K (phosphoinositide 3‐kinase)‐AKT and ERK (extracellular signal‐regulated kinase) signaling pathways, which is a negative regulator of autophagy. Functionally, ANXA6 expression is correlated with LC3 (microtubule‐associated protein 1 light chain 3) expression in cervical cancer, and ANXA6 inhibits tumorigenesis through autophagy induction. Our results reveal an important mechanism for ANXA6 in tumor suppression and autophagy regulation. Autophagy is an intracellular degradation pathway conserved in eukaryotes. ANXA6 (annexin A6) belongs to a family of calcium‐dependent membrane and phospholipid binding proteins. Here, we identify ANXA6 as a newly synthesized protein in starvation‐induced autophagy and validate it as a novel autophagy modulator that regulates autophagosome formation. ANXA6 knockdown attenuates starvation‐induced autophagy and restoration of its expression enhances autophagy. GO (gene ontology) analysis of ANXA6 targets showed that ANXA6 interacts with many RAB GTPases and targets endocytic and phagocytosis pathways, indicating that ANXA6 exert its function through protein trafficking. ATG9A (autophagy related 9A) is the sole multi‐spanning transmembrane protein and its trafficking through the recycling endosomes is an essential step for autophagosome formation. Our results showed that under starvation condition, ANXA6 enables appropriate ATG9A trafficking from endosomes to autophagosomes through RAB proteins or F‐actin. In addition, restoration of ANXA6 expression suppresses mTOR (mammalian target of rapamycin) activity through the inhibition of the PI3K (phosphoinositide 3‐kinase)‐AKT and the ERK (extracellular signal‐regulated kinase) signaling pathway, which is a negative regulator of autophagy. Functionally, ANXA6 expression is correlated with LC3 (microtubule‐associated protein 1 light chain 3) expression in cervical cancer and ANXA6 inhibits tumourigenesis through autophagy induction. Our results reveal an important mechanism for ANXA6 in tumor suppression and autophagy regulation.
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DOI：
10.1111/j.1600-0854.2011.01305.x
发表时间：
2012-02
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Eden ER;Huang F;Sorkin A;Futter CE
通讯作者：
Futter CE
DOI：
10.1016/j.biocel.2009.12.020
发表时间：
2010-05-01
影响因子：
4
作者：
Grewal, Thomas;Koese, Meryem;Enrich, Carlos
通讯作者：
Enrich, Carlos
影响因子：
--
作者：
Corbier, Camille;Sellier, Chantal
通讯作者：
Sellier, Chantal
DOI：
10.1007/978-3-319-55858-5_14
发表时间：
2017-01-01
期刊：
MEMBRANE DYNAMICS AND CALCIUM SIGNALING
影响因子：
--
作者：
Enrich, Carlos;Rentero, Carles;Grewal, Thomas
通讯作者：
Grewal, Thomas
影响因子：
64.5
作者：
Huttlin EL;Ting L;Bruckner RJ;Gebreab F;Gygi MP;Szpyt J;Tam S;Zarraga G;Colby G;Baltier K;Dong R;Guarani V;Vaites LP;Ordureau A;Rad R;Erickson BK;Wühr M;Chick J;Zhai B;Kolippakkam D;Mintseris J;Obar RA;Harris T;Artavanis-Tsakonas S;Sowa ME;De Camilli P;Paulo JA;Harper JW;Gygi SP
通讯作者：
Gygi SP