HECT-type ubiquitin ligase ITCH targets Lysosomal-associated Protein Multispanning Transmembrane 5 (LAPTM5) and prevents LAPTM5-mediated cell death

Takaya Ishihara, Jun Inoue, Ken Ichi Kozaki, Issei Imoto, Johji Inazawa

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

LAPTM5 (lysosomal-associated protein multispanning transmembrane 5) is a membrane protein on the intracellular vesicles. We have previously demonstrated that the accumulation of LAPTM5-positive vesicles was closely associated with the programmed cell death occurring during the spontaneous regression of neuroblastomas. Although the accumulation of LAPTM5 protein might occur at the post-translational level, the molecular mechanism has been unclear. Here, we found that the level of LAPTM5 protein is regulated negatively by the degradation through ubiquitination by ITCH, an E3 ubiquitin ligase. ITCH directly binds to the PPxY motif of LAPTM5 via its WW domains and promotes ubiquitination through a HECT-type ligase domain. Overexpression of ITCH led to the degradation of LAPTM5 protein, and conversely, knockdown of ITCH by siRNA resulted in the stabilization of LAPTM5 protein. In addition, the inhibition of ITCH enhanced the cell death occurred by accumulation of LAPTM5 in neuroblastoma cells. These findings suggest that LAPTM5 is a novel substrate in terms of degradation by the ubiquitin ligase ITCH, and this system might act as a negative regulator in the spontaneous regression of neuroblastomas by preventing LAPTM5-mediated cell death.

Original languageEnglish
Pages (from-to)44086-44094
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number51
DOIs
Publication statusPublished - Dec 23 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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