ANKRD13a controls early cell-death checkpoint by interacting with RIP1 independent of NF-κB

  • Cell Death Differ. 2022 Jun;29(6):1152-1163. doi: 10.1038/s41418-021-00906-9.
Minho Won   #  1  2 ,  Kyeong Ah Park   #  1 ,  Sup Kim  3 ,  Eunjin Ju  1 ,  Youngbok Ko  4 ,  Heonjong Yoo  4 ,  Hyunju Ro  5 ,  Jaeseob Lee  6 ,  Junseo Oh  6 ,  Eun Gyo Lee  2 ,  Sang Yean Kim  7 ,  Suk Woo Nam  7 ,  Han-Ming Shen  8 ,  Min-Kyung Yeo  9 ,  Jin Man Kim  9 ,  Gang Min Hur  10
Affiliations
  • 1. Department of Pharmacology and Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • 2. Biotechnology Process Engineering Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, 28116, Republic of Korea.
  • 3. Department of Radiation Oncology, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • 4. Department of Obstetrics and Gynecology, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • 5. Department of Biological Sciences, College of Biosciences and Biotechnology, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 6. Department of Biomedical Science, Korea University Graduate School, Seoul, 02841, Republic of Korea.
  • 7. Department of Pathology, College of Medicine, The Catholic University, Seoul, 06591, Republic of Korea.
  • 8. Faculty of Health Sciences, University of Macau, Macau, China.
  • 9. Department of Pathology, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • 10. Department of Pharmacology and Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 34839354 DOI: 10.1038/s41418-021-00906-9
Abstract

In TNF signaling, ubiquitination of RIP1 functions as an early cell-death checkpoint, which prevents the spatial transition of the signaling complex from complex-I to death-inducing complex-II. Here, we report that ankyrin repeat domain 13a (ANKRD13a) acts as a novel component of complex-II to set a higher signal threshold for the cytotoxic potential of TNF. ANKRD13a deficiency is sufficient to turn the response to TNF from survival to death by promoting the formation of complex-II without affecting NF-κB activation. ANKRD13a binds to ubiquitinated-RIP1 via its UIM, and subsequently limits the association of FADD and Caspase-8 with RIP1. Moreover, high ANKRD13a expression is inversely correlated with apoptotic phenotypes in ovarian Cancer tissues and is associated with poor prognosis. Our work identifies ANKRD13a as a novel gatekeeper of the early cell-death checkpoint, which may function as part of an escape mechanism from cell death in some cancers.

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