title: N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting.
abstract: BACKGROUND
  The epidermis forms a critical barrier that is maintained by orchestrated programs of proliferation, differentiation, and cell death. Gene mutations that disturb this turnover process may cause skin diseases. Human GASDERMIN A (GSDMA) is frequently silenced in gastric cancer cell lines and its overexpression has been reported to induce apoptosis. GSDMA has also been linked with airway hyperresponsiveness in genetic association studies. The function of GSDMA in the skin was deduced by dominant mutations in mouse gasdermin A3 (Gsdma3), which caused skin inflammation and hair loss. However, the mechanism for the autosomal dominance of Gsdma3 mutations and the mode of Gsdma3's action remain unanswered.
  
  
  RESULTS
  We demonstrated a novel function of Gsdma3 in modulating mitochondrial oxidative stress. We showed that Gsdma3 is regulated by intramolecular fold-back inhibition, which is disrupted by dominant mutations in the C-terminal domain. The unmasked N-terminal domain of Gsdma3 associates with Hsp90 and is delivered to mitochondrial via mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and causes increased production of mitochondrial reactive oxygen species (ROS), dissipation of mitochondrial membrane potential, and mitochondrial permeability transition (MPT). Overexpression of the C-terminal domain of Gsdma3 as well as pharmacological interventions of mitochondrial translocation, ROS production, and MPT pore opening alleviate the cell death induced by Gsdma3 mutants.
  
  
  CONCLUSIONS
  Our results indicate that the genetic mutations in the C-terminal domain of Gsdma3 are gain-of-function mutations which unmask the N-terminal functional domain of Gsdma3. Gsdma3 regulates mitochondrial oxidative stress through mitochondrial targeting. Since mitochondrial ROS has been shown to promote epidermal differentiation, we hypothesize that Gsdma3 regulates context-dependent response of keratinocytes to differentiation and cell death signals by impinging on mitochondria.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Rd., Zhunan, Miaoli County, 35053, Taiwan. ltyang@nhri.org.tw.
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Lin
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Rd., Zhunan, Miaoli County, 35053, Taiwan. ltyang@nhri.org.tw.
authors.forename: Hsien-Yi
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Rd., Zhunan, Miaoli County, 35053, Taiwan. ltyang@nhri.org.tw.
authors.forename: Cheng-Chin
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, 35 Keyan Rd., Zhunan, Miaoli County, 35053, Taiwan. ltyang@nhri.org.tw.|Graduate Institute of Molecular Systems Biomedicine, China Medical University, 91 Hsueh-Shih Rd, Taichung, 40402, Taiwan. ltyang@nhri.org.tw.
authors.forename: Liang-Tung
authors.initials: LT
authors.lastname: Yang
mesh_terms: D000818:Animals; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018384:Oxidative Stress / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000094524:Gasdermins
chemical_list: D018841:HSP90 Heat-Shock Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; C499121:Gsdma3 protein, mouse; D000094524:Gasdermins; C547760:TRAP-1 protein, mouse; C559261:Tom70 protein, mouse