GADD34 induces cell death through inactivation of Akt following traumatic brain injury

• Published in: Cell death & disease Vol. 4; no. 8; p. e754
• Main Authors: Farook, J M, Shields, J, Tawfik, A, Markand, S, Sen, T, Smith, S B, Brann, D, Dhandapani, K M, Sen, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2013; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/378/1934; 631/80/86; 692/699/375/1345; Activating Transcription Factor 4 - metabolism; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Brain Injuries - enzymology; Cell Biology; Cell Culture; Cell death; Cells, Cultured; Cerebral Cortex - enzymology; Cerebral Cortex - pathology; Endoplasmic Reticulum Stress; Excitatory Amino Acid Agonists - pharmacology; Homeostasis; Immunology; Life Sciences; Male; Mice; Mice, Inbred C57BL; N-Methylaspartate - pharmacology; Neurons - physiology; Original; original-article; Phosphorylation; Primary Cell Culture; Promoter Regions, Genetic; Protein Binding; Protein Phosphatase 1 - genetics; Protein Phosphatase 1 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; TNF Receptor-Associated Factor 6 - metabolism; Transcriptional Activation; Ubiquitination; GADD34; TBI; Akt; cell death; TRAF6
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2013.280

Neuronal cell death contributes significantly to the pathology of traumatic brain injury (TBI) irrespective of the mode or severity of the injury. Activation of a pro-survival protein, Akt, is known to be regulated by an E3 ligase TRAF6 through a process of ubiquitination-coupled phosphorylation at its T308 residue. Here we show that upregulation of a pro-apototic protein, GADD34, attenuates TRAF6-mediated Akt activation in a controlled cortical impact model of TBI in mice. TBI induces the expression of GADD34 by stimulating binding of a stress inducible transcription factor, ATF4, to the GADD34 promoter. GADD34 then binds with TRAF6 and prevents its interaction with Akt. This event leads to retention of Akt in the cytosol and prevents phosphorylation at the T308 position. Finally,
in vivo
depletion of GADD34 using a lentiviral knockdown approach leads to a rescue of Akt activation and markedly attenuates TBI-induced cell death.