S-glutathionylation activates STIM1 and alters mitochondrial homeostasis.
Oxidant stress influences many cellular processes, including cell growth, differentiation, and cell death. A well-recognized link between these processes and oxidant stress is via alterations in Ca(2+) signaling. However, precisely how oxidants influence Ca(2+) signaling remains unclear. Oxidant stress led to a phenotypic shift in Ca(2+) mobilization from an oscillatory to a sustained elevated pattern via calcium release-activated calcium (CRAC)-mediated capacitive Ca(2+) entry, and stromal interaction molecule 1 (STIM1)- and Orai1-deficient cells are resistant to oxidant stress. Functionally, oxidant-induced Ca(2+) entry alters mitochondrial Ca(2+) handling and bioenergetics and triggers cell death. STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress and evokes constitutive Ca(2+) entry independent of intracellular Ca(2+) stores. These experiments reveal that cysteine 56 is a sensor for oxidant-dependent activation of STIM1 and demonstrate a molecular link between oxidant stress and Ca(2+) signaling via the CRAC channel.
Hawkins
Brian J
BJ
Department of Biochemistry, Temple University, Philadelphia, PA 19140, USA.
Irrinki
Krishna M
KM
Mallilankaraman
Karthik
K
Lien
Yu-Chin
YC
Wang
Youjun
Y
Bhanumathy
Cunnigaiper D
CD
Subbiah
Ramasamy
R
Ritchie
Michael F
MF
Soboloff
Jonathan
J
Baba
Yoshihiro
Y
Kurosaki
Tomohiro
T
Joseph
Suresh K
SK
Gill
Donald L
DL
Madesh
Muniswamy
M
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002645:Chickens; D002522:Chlorocebus aethiops; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*
D008565:Membrane Proteins; D005978:Glutathione