PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3

Hae Sook Noh, Young Sool Hah, Sahib Zada, Ji Hye Ha, Gyujin Sim, Jin Seok Hwang, Trang Huyen Lai, Huynh Quoc Nguyen, Jae-Yong Park, Hyun Joon Kim, June Ho Byun, Jong Ryeal Hahm, Kee Ryeon Kang, Deok Ryong Kim

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Autophagy plays a critical role in maintaining cell homeostasis in response to various stressors through protein conjugation and activation of lysosome-dependent degradation. MAP1LC3B/LC3B (microtubule- associated protein 1 light chain 3 β) is conjugated with phosphatidylethanolamine (PE) in the membranes and regulates initiation of autophagy through interaction with many autophagy-related proteins possessing an LC3-interacting region (LIR) motif, which is composed of 2 hydrophobic amino acids (tryptophan and leucine) separated by 2 non-conserved amino acids (WXXL). In this study, we identified a new putative LIR motif in PEBP1/RKIP (phosphatidylethanolamine binding protein 1) that was originally isolated as a PE-binding protein and also a cellular inhibitor of MAPK/ERK signaling. PEBP1 was specifically bound to PE-unconjugated LC3 in cells, and mutation (WXXL mutated to AXXA) of this LIR motif disrupted its interaction with LC3 proteins. Interestingly, overexpression of PEBP1 significantly inhibited starvation-induced autophagy by activating the AKT and MTORC1 (mechanistic target of rapamycin [serine/threonine kinase] complex 1) signaling pathway and consequently suppressing the ULK1 (unc-51 like autophagy activating kinase 1) activity. In contrast, ablation of PEBP1 expression dramatically promoted the autophagic process under starvation conditions. Furthermore, PEBP1 lacking the LIR motif highly stimulated starvation-induced autophagy through the AKT-MTORC1-dependent pathway. PEBP1 phosphorylation at Ser153 caused dissociation of LC3 from the PEBP1-LC3 complex for autophagy induction. PEBP1-dependent suppression of autophagy was not associated with the MAPK pathway. These findings suggest that PEBP1 can act as a negative mediator in autophagy through stimulation of the AKT-MTORC1 pathway and direct interaction with LC3.

Original languageEnglish
Pages (from-to)2183-2196
Number of pages14
JournalAutophagy
Volume12
Issue number11
DOIs
Publication statusPublished - 2016 Nov 1

    Fingerprint

Keywords

  • autophagy
  • ERK pathway
  • LC3
  • LIR motif
  • MTOR
  • PEBP1/RKIP

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Noh, H. S., Hah, Y. S., Zada, S., Ha, J. H., Sim, G., Hwang, J. S., Lai, T. H., Nguyen, H. Q., Park, J-Y., Kim, H. J., Byun, J. H., Hahm, J. R., Kang, K. R., & Kim, D. R. (2016). PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3. Autophagy, 12(11), 2183-2196. https://doi.org/10.1080/15548627.2016.1219013