Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex

Liang Weng; Yi-Peng Han; Atsushi Enomoto; Yasuyuki Kitaura; Shushi Nagamori; Yoshikatsu Kanai; Naoya Asai; Jian An; Maki Takagishi; Masato Asai; Shinji Mii; Takashi Masuko; Yoshiharu Shimomura; Masahide Takahashi

doi:10.1371/journal.pbio.2005090

Negative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex

PLoS Biol. 2018 Mar 14;16(3):e2005090. doi: 10.1371/journal.pbio.2005090. eCollection 2018 Mar.

Authors

Affiliations

¹ Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
² Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
³ Laboratory of Biomolecular Dynamics, Department of Collaborative Research, Nara Medical University, Kashihara, Nara, Japan.
⁴ Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
⁵ Department of Respiratory Medicine, Xiangya Hospital, Central South University, Kaifu District, Changsha, China.
⁶ Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Higashiosaka, Osaka, Japan.
⁷ Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Abstract

Amino acid signaling mediated by the activation of mechanistic target of rapamycin complex 1 (mTORC1) is fundamental to cell growth and metabolism. However, how cells negatively regulate amino acid signaling remains largely unknown. Here, we show that interaction between 4F2 heavy chain (4F2hc), a subunit of multiple amino acid transporters, and the multifunctional hub protein girders of actin filaments (Girdin) down-regulates mTORC1 activity. 4F2hc interacts with Girdin in mitogen-activated protein kinase (MAPK)- and amino acid signaling-dependent manners to translocate to the lysosome. The resultant decrease in cell surface 4F2hc leads to lowered cytoplasmic glutamine (Gln) and leucine (Leu) content, which down-regulates amino acid signaling. Consistently, Girdin depletion augments amino acid-induced mTORC1 activation and inhibits amino acid deprivation-induced autophagy. These findings uncovered the mechanism underlying negative regulation of amino acid signaling, which may play a role in tightly regulated cell growth and metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Down-Regulation
Fusion Regulatory Protein 1, Heavy Chain / metabolism
Fusion Regulatory Protein 1, Heavy Chain / physiology*
HeLa Cells
Humans
Lysosomes / metabolism
MAP Kinase Signaling System*
Mechanistic Target of Rapamycin Complex 1 / physiology
Mice
Microfilament Proteins / metabolism
Microfilament Proteins / physiology*
Phosphorylation
Signal Transduction*
Ubiquitination
Vesicular Transport Proteins / metabolism
Vesicular Transport Proteins / physiology*

Substances

Fusion Regulatory Protein 1, Heavy Chain
Microfilament Proteins
Vesicular Transport Proteins
girdin protein, mouse
Mechanistic Target of Rapamycin Complex 1

Grants and funding

The Ministry of Education, Culture, Sports, Science and Technology of Japan (grant number 15K21061). Recieved by LW. The Ministry of Education, Culture, Sports, Science and Technology of Japan (grant number 15H04719). Recieved by AE. The Ministry of Education, Culture, Sports, Science and Technology of Japan (grant number 26221304). Recieved by M. Takahashi. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.