Tumor suppressor KIF1Bβ regulates mitochondrial apoptosis in collaboration with YME1L1

Koji Ando, Tomoki Yokochi, Akira Mukai, Gao Wei, Yuanyuan Li, Sonja Kramer, Toshinori Ozaki, Yoshihiko Maehara, Akira Nakagawara

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

KIF1Bβ, a member of the kinesin superfamily of motor proteins, is a haploinsufficient tumor suppressor mapped to chromosome 1p36.2, which is frequently deleted in neural crest–derived tumors, including neuroblastoma and pheochromocytoma. While KIF1Bβ acts downstream of the nerve growth factor (NGF) pathway to induce apoptosis, further molecular functions of this gene product have largely been unexplored. In this study, we report that KIF1Bβ destabilizes the morphological structure of mitochondria, which is critical for cell survival and apoptosis. We identified YME1L1, a mitochondrial metalloprotease responsible for the cleavage of the mitochondrial GTPase OPA1, as a physical interacting partner of KIF1Bβ. KIF1Bβ interacted with YME1L1 through its death-inducing region, as initiated the protease activity of YME1L1 to cleave the long forms of OPA1, resulting in mitochondrial fragmentation. Overexpression of YME1L1 promoted apoptosis, while knockdown of YME1L1 promoted cell growth. High YME1L1 expression was significantly associated with a better prognosis in neuroblastoma. Furthermore, in NGF-deprived PC12 cells, KIF1Bβ and YME1L1 were upregulated, accompanied by mitochondrial fragmentation and apoptotic cell death. Small interfering RNA–mediated knockdown of either protein alone, however, remarkably inhibited the NGF depletion–induced apoptosis. Our findings indicate that tumor suppressor KIF1Bβ plays an important role in intrinsic mitochondria–mediated apoptosis through the regulation of structural and functional dynamics of mitochondria in collaboration with YME1L1. Dysfunction of the KIF1Bβ/YME1L1/OPA1 mechanism may be involved in malignant biological features of neural crest–derived tumors as well as the initiation and progression of neurodegenerative diseases.

Original languageEnglish
Pages (from-to)1134-1144
Number of pages11
JournalMolecular Carcinogenesis
Volume58
Issue number7
DOIs
Publication statusPublished - Jul 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

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    Ando, K., Yokochi, T., Mukai, A., Wei, G., Li, Y., Kramer, S., Ozaki, T., Maehara, Y., & Nakagawara, A. (2019). Tumor suppressor KIF1Bβ regulates mitochondrial apoptosis in collaboration with YME1L1. Molecular Carcinogenesis, 58(7), 1134-1144. https://doi.org/10.1002/mc.22997