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Critical Stress Response Program Controls the Regenerative Potential of NSPCs

Review of “Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification” from Nature Communications by Stuart P. Atkinson

During their lifetime, neural stem/progenitor cells (NSPCs) face a barrage of stressors that negatively impact their function and deplete their number [1, 2]. As part of cellular defenses against a range of age-related stressors, Forkhead box protein O (FOXO) transcription factors both sense stress and promote resistance [3]. Importantly, studies have also described how FOXO transcription factor expression in the central nervous system plays a crucial role in preserving NSPC pools [4, 5].

Researchers led by Jihye Paik (Weil Cornell Medicine, New York, NY, USA) recently sought to define just how oxidative stress impacts FOXO activation in NSPCs and how this contributes to the neuroprotective response by focusing on type-I interferon (IFN-I), which forms part of an innate immune response induced by several pattern recognition receptors [6]. The choice of this specific focus derived from studies demonstrating a link between the IFN-I response, NSPC quiescence, and the suppression of differentiation [1, 7], and a correlation between increased IFN-I signaling in the brain, aging, and oxidative stress [1].

In their new study [8], Hwang et al. now describe how a complex signaling cascade involving FOXO3 and IFN-I represents a critical stress response program that controls the long-term regenerative potential of NSPCs under oxidative conditions.

The authors report that an acute elevation in redox potential in NSPCs (as induced by treatment with pro-oxidants) activated the FOXO3 transcription factor via oxidation at the evolutionarily conserved Cys31 residue, which modulates FOXO3 nucleo-cytoplasmic shuttling and downstream signaling. FOXO3 activation subsequently induced the transcriptional upregulation of glycine-N-methyltransferase (GNMT) and the metabolic depletion of s-adenosylmethionine (SAM). The oxidative stress-mediated reduction in the intracellular levels of this crucial methyl group transfer co-substrate then prompted a global reduction of the methylation of lysine 4 on histone H3, a modification associated with gene transcription; however, SAM depletion also disrupted the carboxymethylation and maturation of nuclear lamin to induce cytosolic DNA leakage. The presence of chromatin fragments into the cytosol of NSPCs then prompted the activation of the cGAS–STING pathway, a component of the innate immune system that triggers the expression of inflammatory genes in response to the presence of cytosolic DNA, and a subsequent IFN-I response that inhibits NSPC differentiation.

In summary, these findings suggest the existence of a FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I stress response program that regulates the long-term regenerative potential of NSPCs, which explains how oxidative stress triggers IFN-I response-mediated cellular protective response and homeostasis under pathophysiological conditions.

For more on how NSPCs continue functioning after a lifetime of stress, stay tuned to the Stem Cells Portal!

References

  1. Kalamakis G, Brüne D, Ravichandran S, et al., Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain. Cell 2019;176:1407-1419.e14.
  2. Zipp F and Aktas O, The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends in Neurosciences 2006;29:518-527.
  3. Martins R, Lithgow GJ, and Link W, Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell 2016;15:196-207.
  4. Renault VM, Rafalski VA, Morgan AA, et al., FoxO3 Regulates Neural Stem Cell Homeostasis. Cell Stem Cell 2009;5:527-539.
  5. Paik J-h, Ding Z, Narurkar R, et al., FoxOs Cooperatively Regulate Diverse Pathways Governing Neural Stem Cell Homeostasis. Cell Stem Cell 2009;5:540-553.
  6. Takeuchi O and Akira S, Pattern Recognition Receptors and Inflammation. Cell 2010;140:805-820.
  7. Baruch K, Deczkowska A, David E, et al., Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 2014;346:89.
  8. Hwang I, Uchida H, Dai Z, et al., Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification. Nature Communications 2021;12:640.