Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor

Mickael Diallo; Constança Pimenta; Fernanda Murtinheira; Daniela Martins-Alves; Francisco R Pinto; André Abrantes da Costa; Ricardo Letra-Vilela; Vanesa Martin; Carmen Rodriguez; Mário S Rodrigues; Federico Herrera

doi:10.1007/s13402-023-00911-9

Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor

Cell Oncol (Dordr). 2023 Dec 27. doi: 10.1007/s13402-023-00911-9. Online ahead of print.

Authors

Affiliations

¹ BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal.
² MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal.
³ Departamento de Morfología y Biología Celular, Facultad de Medicina, University of Oviedo, c/Julian Claveria, Oviedo, 33006, Spain.
⁴ Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
⁵ BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal. fherrera@fc.ul.pt.

PMID: 38150153
DOI: 10.1007/s13402-023-00911-9

Abstract

STAT3 is a pleiotropic transcription factor overactivated in 70% of solid tumours. We have recently reported that inactivating mutations on residues susceptible to post-translational modifications (PTMs) in only one of the monomers (i.e. asymmetric) caused changes in the cellular distribution of STAT3 homodimers. Here, we used more controlled experimental conditions, i.e. without the interference of endogenous STAT3 (STAT3-/- HeLa cells) and in the presence of a defined cytokine stimulus (Leukemia Inhibitory Factor, LIF), to provide further evidence that asymmetric PTMs affect the nuclear translocation of STAT3 homodimers. Time-lapse microscopy for 20 min after LIF stimulation showed that S727 dephosphorylation (S727A) and K685 inactivation (K685R) slightly enhanced the nuclear translocation of STAT3 homodimers, while K49 inactivation (K49R) delayed STAT3 nuclear translocation. Our findings suggest that asymmetrically modified STAT3 homodimers could be a new level of STAT3 regulation and, therefore, a potential target for cancer therapy.

Keywords: Homodimerization; Leukemia inhibitory factor; Post-translational modifications; STAT3.