TIA-1 Self-Multimerization, Phase Separation, and Recruitment into Stress Granules Are Dynamically Regulated by Zn2

Joseph B Rayman; Kevin A Karl; Eric R Kandel

doi:10.1016/j.celrep.2017.12.036

TIA-1 Self-Multimerization, Phase Separation, and Recruitment into Stress Granules Are Dynamically Regulated by Zn²

Cell Rep. 2018 Jan 2;22(1):59-71. doi: 10.1016/j.celrep.2017.12.036.

Authors

Joseph B Rayman¹, Kevin A Karl², Eric R Kandel³

Affiliations

¹ Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA.
² Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute at Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA.
³ Department of Neuroscience, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute at Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA; Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA. Electronic address: erk5@columbia.edu.

PMID: 29298433
DOI: 10.1016/j.celrep.2017.12.036

Abstract

Stress granules are non-membranous structures that transiently form in the cytoplasm during cellular stress, where they promote translational repression of non-essential RNAs and modulate cell signaling by sequestering key signal transduction proteins. These and other functions of stress granules facilitate an adaptive cellular response to environmental adversity. A key component of stress granules is the prion-related RNA-binding protein, T cell intracellular antigen-1 (TIA-1). Here, we report that recombinant TIA-1 undergoes rapid multimerization and phase separation in the presence of divalent zinc, which can be reversed by the zinc chelator, TPEN. Similarly, the formation and maintenance of TIA-1-positive stress granules in arsenite-treated cells are inhibited by TPEN. In addition, Zn²⁺ is released in cells treated with arsenite, before stress granule formation. These findings suggest that Zn²⁺ is a physiological ligand of TIA-1, acting as a stress-inducible second messenger to promote multimerization of TIA-1 and subsequent localization into stress granules.

Keywords: TIA-1; TIA1; cellular stress; functional prion; phase separation; stress granules; zinc regulation.

Publication types

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

MeSH terms

Arsenites / pharmacology*
Cell Line
Cytoplasmic Granules* / chemistry
Cytoplasmic Granules* / genetics
Cytoplasmic Granules* / metabolism
Humans
Protein Multimerization / drug effects*
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Second Messenger Systems / drug effects*
T-Cell Intracellular Antigen-1* / chemistry
T-Cell Intracellular Antigen-1* / genetics
T-Cell Intracellular Antigen-1* / metabolism
Zinc* / chemistry
Zinc* / metabolism

Substances

Arsenites
Recombinant Proteins
T-Cell Intracellular Antigen-1
TIA1 protein, human
Zinc
arsenite

Grants and funding

HHMI/Howard Hughes Medical Institute/United States