Mechanistic study of TRPM2-Ca2+-CAMK2-BECN1 signaling in oxidative stress-induced autophagy inhibition

Qian Wang, Wenjing Guo, Baixia Hao, Xianli Shi, Yingying Lu, Connie W.M. Wong, Victor W.S. Ma, Timothy T.C. Yip, Joseph S.K. Au, Quan Hao, King Ho Cheung, Wutian Wu, Gui Rong Li, Jianbo Yue*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

71 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) have been commonly accepted as inducers of autophagy, and autophagy in turn is activated to relieve oxidative stress. Yet, whether and how oxidative stress, generated in various human pathologies, regulates autophagy remains unknown. Here, we mechanistically studied the role of TRPM2 (transient receptor potential cation channel subfamily M member 2)-mediated Ca2+ influx in oxidative stress-mediated autophagy regulation. On the one hand, we demonstrated that oxidative stress triggered TRPM2-dependent Ca2+ influx to inhibit the induction of early autophagy, which renders cells more susceptible to death. On the other hand, oxidative stress induced autophagy (and not cell death) in the absence of the TRPM2-mediated Ca2+ influx. Moreover, in response to oxidative stress, TRPM2-mediated Ca2+ influx activated CAMK2 (calcium/calmodulin dependent protein kinase II) at levels of both phosphorylation and oxidation, and the activated CAMK2 subsequently phosphorylated BECN1/Beclin 1 on Ser295. Ser295 phosphorylation of BECN1 in turn decreased the association between BECN1 and PIK3C3/VPS34, but induced binding between BECN1 and BCL2. Clinically, acetaminophen (APAP) overdose is the most common cause of acute liver failure worldwide. We demonstrated that APAP overdose also activated ROS-TRPM2-CAMK2-BECN1 signaling to suppress autophagy, thereby causing primary hepatocytes to be more vulnerable to death. Inhibiting the TRPM2-Ca2+-CAMK2 cascade significantly mitigated APAP-induced liver injury. In summary, our data clearly demonstrate that oxidative stress activates the TRPM2-Ca2+-CAMK2 cascade to phosphorylate BECN1 resulting in autophagy inhibition.

Original languageEnglish
Pages (from-to)1340-1354
Number of pages15
JournalAutophagy
Volume12
Issue number8
DOIs
Publication statusPublished - 2 Aug 2016

User-Defined Keywords

  • acetaminophen
  • autophagy
  • BECN1
  • Ca2+
  • CAMK2
  • oxidative stress
  • reactive oxygen species
  • TRPM2

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