REDD1 interacts with AIF and regulates mitochondrial reactive oxygen species generation in the keratinocyte response to UVB

Non-melanoma skin cancer (NMSC) incidence is rising, especially in high-risk, immunocompromised groups such as organ transplant patients, who often develop numerous, aggressive cutaneous squamous cell carcinomas. Identifying the pathways that support NMSC development will result in new approaches for prevention and therapy. Our goal is to define the function of REDD1 (Regulated in DNA Damage and Development 1) in the UVB stress response. REDD1 is rapidly induced by a variety of stressors to repress mechanistic target of rapamycin complex I (mTORC1), and it has been reported that REDD1 loss causes dysfunctional mitochondria with increased reactive oxygen species (ROS) and impaired oxidative phosphorylation (OXPHOS). We now show that knockout of REDD1 in human keratinocytes sensitizes them to UVB-induced apoptosis in an mTORC1-independent manner and intensifies mitochondrial ROS generation. Upon REDD1 knockout, we observe reduced levels of apoptosis inducing factor (AIF), a mitochondrial intermembrane space NADH oxidase that is required for electron transport chain Complex I biogenesis. Further, we show that keratinocyte REDD1 interacts with both AIF and the mitochondrial import protein CHCHD4, a direct binding partner of AIF that ensures functional OXPHOS. Our results support the hypothesis that REDD1 is part of a mitochondrial complex that protects cells from UVB-induced ROS toxicity and suggest novel therapeutic targets for prevention and therapy of NMSC.

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Work Title REDD1 interacts with AIF and regulates mitochondrial reactive oxygen species generation in the keratinocyte response to UVB
Access
Open Access
Creators
  1. Robert P. Feehan
  2. Catherine Coleman
  3. Shauna Ebanks
  4. Charles Lang
  5. Lisa M. Shantz
Keyword
  1. REDD1
  2. AIF
  3. UVB
  4. mTOR
  5. Non-melanoma skin cancer
  6. Apoptosis
License CC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives)
Work Type Article
Publisher
  1. Biochemical and Biophysical Research Communications
Publication Date May 27, 2022
Publisher Identifier (DOI)
  1. https://doi.org/10.1016/j.bbrc.2022.05.066
Deposited August 04, 2022

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Version 1
published

  • Created
  • Added Feehan_et_al_accepted_manuscript.docx
  • Added Supplementary_information.docx
  • Added Creator Robert P. Feehan
  • Added Creator Catherine Coleman
  • Added Creator Shauna Ebanks
  • Added Creator Charles Lang
  • Added Creator Lisa M. Shantz
  • Published
  • Updated Keyword, Publication Date Show Changes
    Keyword
    • REDD1, AIF, UVB, mTOR, Non-melanoma skin cancer, Apoptosis
    Publication Date
    • 2022-05-20
    • 2022-05-27
  • Updated