Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation.
Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation.
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DOI：
10.1080/15548627.2017.1287653
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发表时间：
2017-05-04
期刊：
影响因子：
13.3
通讯作者：
Florey O
中科院分区：
文献类型：
--
作者：
Jacquin E;Leclerc-Mercier S;Judon C;Blanchard E;Fraitag S;Florey O
调节典型巨噬/自噬的治疗效益是一种新兴的策略，医学和制药的兴趣。许多药物通过靶向溶酶体功能来抑制自噬通量，而其他药物则被开发用于激活该途径。在这里，我们报告了一个令人惊讶的发现，许多治疗相关的自噬调节剂具有溶酶体性和离子载体特性，被归类为典型自噬抑制剂，也能够激活平行的非典型自噬途径，驱动内溶酶体膜上的MAP1LC3/LC3脂化。此外，我们通过局部麻醉利多卡因和人体皮肤活检，首次提供了支持药物诱导的体内非典型自噬的证据。此外，我们发现一些已发表的自噬和有丝自噬诱导剂也是非典型自噬的有效激活剂。总之，我们的数据提出了关于LC3脂化数据的解释和自噬调节剂的使用的重要问题，并强调需要更好地理解非典型自噬的功能后果。
The modulation of canonical macroautophagy/autophagy for therapeutic benefit is an emerging strategy of medical and pharmaceutical interest. Many drugs act to inhibit autophagic flux by targeting lysosome function, while others were developed to activate the pathway. Here, we report the surprising finding that many therapeutically relevant autophagy modulators with lysosomotropic and ionophore properties, classified as inhibitors of canonical autophagy, are also capable of activating a parallel noncanonical autophagy pathway that drives MAP1LC3/LC3 lipidation on endolysosomal membranes. Further, we provide the first evidence supporting drug-induced noncanonical autophagy in vivo using the local anesthetic lidocaine and human skin biopsies. In addition, we find that several published inducers of autophagy and mitophagy are also potent activators of noncanonical autophagy. Together, our data raise important issues regarding the interpretation of LC3 lipidation data and the use of autophagy modulators, and highlight the need for a greater understanding of the functional consequences of noncanonical autophagy.