Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Wei-jia Wang; Yuan Wang; Hang-zi Chen; Yong-zhen Xing; Feng-wei Li; Qian Zhang; Bo Zhou; Hong-kui Zhang; Jie Zhang; Xue-li Bian; Li Li; Yuan Liu; Bi-xing Zhao; Yan Chen; Rong Wu; An-zhong Li; Lu-ming Yao; Ping Chen; Yi Zhang; Xu-yang Tian; Friedrich Beermann; Mian Wu; Jiahuai Han; Pei-qiang Huang; Tianwei Lin; Qiao Wu

doi:10.1038/nchembio.1406

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Nat Chem Biol. 2014 Feb;10(2):133-40. doi: 10.1038/nchembio.1406. Epub 2013 Dec 8.

Authors

Wei-jia Wang¹, Yuan Wang¹, Hang-zi Chen¹, Yong-zhen Xing¹, Feng-wei Li¹, Qian Zhang², Bo Zhou², Hong-kui Zhang³, Jie Zhang³, Xue-li Bian², Li Li², Yuan Liu², Bi-xing Zhao², Yan Chen², Rong Wu², An-zhong Li², Lu-ming Yao², Ping Chen², Yi Zhang², Xu-yang Tian², Friedrich Beermann⁴, Mian Wu⁵, Jiahuai Han², Pei-qiang Huang³, Tianwei Lin², Qiao Wu²

Affiliations

¹ 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China. [2].
² State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
³ Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.
⁴ ISREC, Swiss Institute for Experimental Cancer Research, SV EPFL, Lausanne, Switzerland.
⁵ Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.

PMID: 24316735
DOI: 10.1038/nchembio.1406

Abstract

Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

Publication types

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

MeSH terms

Animals
Autophagy*
Cell Line, Tumor
Crystallography, X-Ray
Disease Models, Animal
Humans
Ketones / chemistry*
Ketones / pharmacology
Melanoma / drug therapy
Membrane Proteins / metabolism
Mice
Mitochondria / physiology*
Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
Protein Conformation
Proto-Oncogene Proteins / metabolism
Pyrogallol / analogs & derivatives*
Pyrogallol / chemistry
Pyrogallol / pharmacology
Signal Transduction*
Tumor Suppressor Proteins / metabolism

Substances

1-(3,4,5-trihydroxyphenyl)nonan-1-one
BNIP3L protein, human
Ketones
Membrane Proteins
Nuclear Receptor Subfamily 4, Group A, Member 1
Proto-Oncogene Proteins
Tumor Suppressor Proteins
Pyrogallol

Associated data

PDB/4JGV
PDB/4KZI
PDB/4KZJ
PDB/4KZM
PubChem-Substance/165230472
PubChem-Substance/165230473
PubChem-Substance/165230474
PubChem-Substance/165230475
PubChem-Substance/165230476
PubChem-Substance/165230477
PubChem-Substance/165230478
PubChem-Substance/165230479
PubChem-Substance/165230480
PubChem-Substance/165230481