The CYFIP2 Arg87Cys Mutation Reshapes the Interactome and Alters Stress Fiber-Associated Proteins

Abstract

The Arg87Cys mutation in CYFIP2 has been implicated in early-onset developmental and epileptic encephalopathy (DEE), yet its molecular consequences remain incompletely understood. CYFIP2 functions as part of the WAVE regulatory complex (WRC), where it plays a key role in actin filament polymerization and interacts with RNA-binding proteins (RBPs) to regulate mRNA translation. Previous studies have demonstrated that this mutation alters the structure of CYFIP2, resulting in a gain of function in the WRC. Additionally, the mutation appears to promote the formation of intracellular granules that colocalize with RBPs; however, the impacts of this mutation on these interactions remain unclear. Here, we combined cross-linking mass spectrometry (XL-MS) and label-free quantitative proteomics to investigate how this mutation alters the protein interactome and actin regulatory pathways. XL-MS data revealed exclusive cross-links between actin and tropomyosin isoforms in the Arg87Cys variant, suggesting altered cytoskeletal dynamics. Quantitative proteomic analysis of patient-derived neural progenitor cells corroborated these findings by revealing an increase in the abundance of stress-fiber-associated proteins. Altogether, our results point to a broader impact of CYFIP2 mutations on cytoskeletal organization and protein interaction networks with potential implications beyond the nervous system. This is the first study to our knowledge to suggest a link between the Arg87Cys mutation and dysregulation of stress-fiber-related proteins, indicating possible disruption of other actin-processing pathways.

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BibTeX RIS

BibTeX

@article{biembengut2026cyfip2,
  title = {{The CYFIP2 Arg87Cys Mutation Reshapes the Interactome and Alters Stress Fiber-Associated Proteins}},
  author = {Ísis V. Biembengut and Emanuella de C. Andreassa and Marlon D. M. dos Santos and Isabelle L. Z. Silva and Louise U. Kurt and Patrícia Shigunov and Paulo C. Carvalho and Tatiana A. C. B. de Souza},
  journal = {ACS Omega},
  year = {2026},
  month = oct,
  doi = {10.1021/acsomega.5c12192},
  url = {https://pubs.acs.org/acsodf/article/11/42/64371/5448925/The-CYFIP2-Arg87Cys-Mutation-Reshapes-the},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - The CYFIP2 Arg87Cys Mutation Reshapes the Interactome and Alters Stress Fiber-Associated Proteins
AU  - Ísis V. Biembengut
AU  - Emanuella de C. Andreassa
AU  - Marlon D. M. dos Santos
AU  - Isabelle L. Z. Silva
AU  - Louise U. Kurt
AU  - Patrícia Shigunov
AU  - Paulo C. Carvalho
AU  - Tatiana A. C. B. de Souza
PY  - 2026
DA  - 2026/10/12
JO  - ACS Omega
DO  - 10.1021/acsomega.5c12192
UR  - https://pubs.acs.org/acsodf/article/11/42/64371/5448925/The-CYFIP2-Arg87Cys-Mutation-Reshapes-the
AB  - The Arg87Cys mutation in CYFIP2 has been implicated in early-onset developmental and epileptic encephalopathy (DEE), yet its molecular consequences remain incompletely understood. CYFIP2 functions as part of the WAVE regulatory complex (WRC), where it plays a key role in actin filament polymerization and interacts with RNA-binding proteins (RBPs) to regulate mRNA translation. Previous studies have demonstrated that this mutation alters the structure of CYFIP2, resulting in a gain of function in the WRC. Additionally, the mutation appears to promote the formation of intracellular granules that colocalize with RBPs; however, the impacts of this mutation on these interactions remain unclear. Here, we combined cross-linking mass spectrometry (XL-MS) and label-free quantitative proteomics to investigate how this mutation alters the protein interactome and actin regulatory pathways. XL-MS data revealed exclusive cross-links between actin and tropomyosin isoforms in the Arg87Cys variant, suggesting altered cytoskeletal dynamics. Quantitative proteomic analysis of patient-derived neural progenitor cells corroborated these findings by revealing an increase in the abundance of stress-fiber-associated proteins. Altogether, our results point to a broader impact of CYFIP2 mutations on cytoskeletal organization and protein interaction networks with potential implications beyond the nervous system. This is the first study to our knowledge to suggest a link between the Arg87Cys mutation and dysregulation of stress-fiber-related proteins, indicating possible disruption of other actin-processing pathways.
SN  - 2470-1343
ER  -

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