Enhanced Integrated Stress Response Promotes Myelinating Oligodendrocyte Survival in Response to Interferon-γ

Abstract

The T-cell-derived, pleiotropic cytokine interferon (IFN)-␥ is believed to play a key regulatory role in immune-mediated demyelinating disorders of the central nervous system, including multiple sclerosis and experimental autoimmune encephalomyelitis. Our previous work has demonstrated that the endoplasmic reticulum (ER) stress response modulates the response of oligodendrocytes to this cytokine. The ER stress response activates the pancreatic ER kinase, which coordinates an adaptive program known as the integrated stress response by phosphorylating translation initiation factor 2␣ (eIF2␣). In this study, we found that growth arrest and DNA damage 34 (GADD34), a stress-inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2␣, was selectively up-regulated in myelinating oligodendrocytes in mice that ectopically expressed IFN-␥ in the central nervous system. We also found that a GADD34 mutant strain of mice displayed increased levels of phosphorylated eIF2␣ (p-eIF2␣) in myelinating oligodendrocytes when exposure to IFN-␥, as well as diminished oligodendrocyte loss and hypomyelination. Furthermore, treatment with salubrinal, a small chemical compound that specifically inhibits protein phosphatase 1(PP1)-GADD34 phosphatase activity, increased the levels of p-eIF2␣ and ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN-␥. Thus, our data provide evidence that an enhanced integrated stress response could promote oligodendrocyte survival in immune-mediated demyelination diseases. (Am J Pathol 2008, 173

cFLIP is critical for oligodendrocyte protection from inflammation

“…Activation of ISR, including PERK was reported to be critical in providing protection, 48 although the molecular mechanisms leading to inhibition of cell death were not clear. Unlike previous reports 9,32,33,48 suggesting that protection by IFNγ requires activation of the ISR, we did not observe phosphorylation of PERK and BiP expression induced by IFNγ. This suggests that the UPR was not activated in our system, and that there was no ER stress induced by IFNγ or TNFα.…”

“…In contrast with effects of IFNγ on PKR activation, we found no activation of PKR-like endoplasmic reticulum (ER) kinase (PERK), which was recently implicated in IFNγ-mediated protection of oligodendrocytes 9,32,33 ( Figure 4a). Furthermore, we found no change in expression of the ER chaperone protein BiP (Figure 4e), which is associated with accumulation Figure 1 IFNγ protects GalC + oligodendrocytes from TNFα-induced cell death and inhibits caspase activation.…”

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

“…Autophagy, stimulated via fasting or rapamycin, or an increase in the heat shock response, can improve the phenotype of some PMP22-related neuropathies (Fortun et al, 2007;Rangaraju et al, 2008Rangaraju et al, , 2010Madorsky et al, 2009), and salubrinal enhancement of the integrated stress response (ISR) ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to IFN- (Lin et al, 2008).…”

“…By dephosphorylating eIF2, Gadd34 promotes the GTP exchange by eIF2B on eIF2. Not only does Gadd34 moderate CMT1B neuropathy in the PNS, and interferon--induced demyelination in the CNS (Lin et al, 2008), but also mutations in various subunits of eIF2B cause vanishing white matter disease in the CNS, which is often associated with diffuse oligodendrocyte death (van der Knaap et al, 2006).…”

The Integrated Stress Response in Hypoxia-Induced Diffuse White Matter Injury

“…PERK is also a component of the unfolded protein response (UPR) and phosphorylated eIF2␣ (p-eIF2␣) decreases global protein translation and upregulates cytoprotective gene expression through activating transcription factor 4 (ATF4; Donnelly et al, 2013). ATF4 also increases the expression of the transcription factor CAAT enhancer binding protein homologous protein (CHOP; also known as DDIT3; Harding et al, 2003). CHOP increases the expression of growth and arrest DNA damage 34 (GADD34; also known as PPP1R15A), which forms a complex with protein phosphatase 1 to dephosphorylate eIF2␣ forming a negative feedback loop that dampens the ISR (Novoa et al, 2001).…”