Document Type
Article
Publication Date
8-10-2021
Publication Title
Cell Rep
Keywords
JGM
JAX Source
Cell Rep 2021 Aug 10; 36(6):109512
Volume
36
Issue
6
First Page
109512
Last Page
109512
ISSN
2211-1247
PMID
34380038
DOI
https://doi.org/10.1016/j.celrep.2021.109512
Grant
HL125807, HL142787, EB028898
Abstract
Actinins are strain-sensing actin cross-linkers that are ubiquitously expressed and harbor mutations in human diseases. We utilize CRISPR, pluripotent stem cells, and BioID to study actinin interactomes in human cardiomyocytes. We identify 324 actinin proximity partners, including those that are dependent on sarcomere assembly. We confirm 19 known interactors and identify a network of RNA-binding proteins, including those with RNA localization functions. In vivo and biochemical interaction studies support that IGF2BP2 localizes electron transport chain transcripts to actinin neighborhoods through interactions between its K homology (KH) domain and actinin's rod domain. We combine alanine scanning mutagenesis and metabolic assays to disrupt and functionally interrogate actinin-IGF2BP2 interactions, which reveal an essential role in metabolic responses to pathological sarcomere activation using a hypertrophic cardiomyopathy model. This study expands our functional knowledge of actinin, uncovers sarcomere interaction partners, and reveals sarcomere crosstalk with IGF2BP2 for metabolic adaptation relevant to human disease.
Recommended Citation
Ladha F,
Thakar K,
Pettinato A,
Legere N,
Ghahremani S,
Cohn R,
Romano R,
Meredith E,
Chen Y,
Hinson J.
Actinin BioID reveals sarcomere crosstalk with oxidative metabolism through interactions with IGF2BP2. Cell Rep 2021 Aug 10; 36(6):109512
Comments
This study could not have been completed without the assistance of Bo Reese (UConn Center for Genome Innovation) for RNA sequencing and RIP-seq and Anthony Carcio (The Jackson Laboratory for Genomic Medicine) for flow cytometry. TMT proteomics and quantitative analyses was supported by Sanjukta Thakurta from the Thermo Fisher Center for Multiplexed Proteomics at Harvard Medical School. Proteomics presentation was discussed and reviewed by Dr. Andy Greene of the Jackson Laboratory. Artwork was created using BioRender.
This is an open access article under the CC BY-NC-ND license.