1. Academic Validation
  2. ANKRD13a controls early cell-death checkpoint by interacting with RIP1 independent of NF-κB

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

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.
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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