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

14 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

Autophagy
Starvation
Protein Kinases
Phosphatidylethanolamine Binding Protein
tryptophan-leucine
Amino Acids
Microtubule-Associated Proteins
Protein-Serine-Threonine Kinases
Sirolimus
Lysosomes
Proteins
Homeostasis
Phosphorylation
Light
Mutation
Membranes

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3. / Noh, Hae Sook; Hah, Young Sool; Zada, Sahib; Ha, Ji Hye; Sim, Gyujin; Hwang, Jin Seok; Lai, Trang Huyen; Nguyen, Huynh Quoc; Park, Jae-Yong; Kim, Hyun Joon; Byun, June Ho; Hahm, Jong Ryeal; Kang, Kee Ryeon; Kim, Deok Ryong.

In: Autophagy, Vol. 12, No. 11, 01.11.2016, p. 2183-2196.

Research output: Contribution to journalArticle

Noh, HS, Hah, YS, Zada, S, Ha, JH, Sim, G, Hwang, JS, Lai, TH, Nguyen, HQ, Park, J-Y, Kim, HJ, Byun, JH, Hahm, JR, Kang, KR & Kim, DR 2016, 'PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3', Autophagy, vol. 12, no. 11, pp. 2183-2196. https://doi.org/10.1080/15548627.2016.1219013
Noh, Hae Sook ; Hah, Young Sool ; Zada, Sahib ; Ha, Ji Hye ; Sim, Gyujin ; Hwang, Jin Seok ; Lai, Trang Huyen ; Nguyen, Huynh Quoc ; Park, Jae-Yong ; Kim, Hyun Joon ; Byun, June Ho ; Hahm, Jong Ryeal ; Kang, Kee Ryeon ; Kim, Deok Ryong. / PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3. In: Autophagy. 2016 ; Vol. 12, No. 11. pp. 2183-2196.
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AU - Sim, Gyujin

AU - Hwang, Jin Seok

AU - Lai, Trang Huyen

AU - Nguyen, Huynh Quoc

AU - Park, Jae-Yong

AU - Kim, Hyun Joon

AU - Byun, June Ho

AU - Hahm, Jong Ryeal

AU - Kang, Kee Ryeon

AU - Kim, Deok Ryong

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