Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells

Ankitha Shetty, Santosh D. Bhosale, Subhash Kumar Tripathi, Tanja Buchacher, Rahul Biradar, Omid Rasool, Robert Moulder, Sanjeev Galande, Riitta Lahesmaa*

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Abstrakt

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among the latter, FOSL1 and FOSL2 modulate the effector functions of Th17 cells. However, the molecular mechanisms underlying these effects are unclear, owing to the poorly characterized protein interaction networks of FOSL factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification-mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a significant fraction of these interactors to be associated with RNA-binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17 fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL proteins that potentially govern Th17 cell differentiation and associated pathologies.

OriginalsprogEngelsk
TidsskriftACS Omega
Vol/bind6
Udgave nummer38
Sider (fra-til)24834–24847
ISSN2470-1343
DOI
StatusUdgivet - 28. sep. 2021

Bibliografisk note

Funding Information:
A.S. was supported by Erasmus Mundus Scholarship, University of Turku (UTU), and Council of Scientific & Industrial Research (CSIR), Government of India. S.K.T. was supported by the Juvenile Diabetes Research Foundation Ltd. (JDRF; grant 3-PDF-2018-574-A-N); S.G. received grants from the Centre of Excellence in Epigenetics program (phase II) of the Department of Biotechnology (BT/COE/34/SP17426/2016), Government of India; and the JC Bose Fellowship (JCB/2019/000013) from the Science and Engineering Research Board, Government of India. R.L. received funding from the Academy of Finland (grant nos. 292335, 292482, 298732, 294337, 298998, 31444, 315585, 319280, 329277, 323310, 331790); by grants from the JDRF; the Sigrid Jusélius Foundation (SJF); Jane and Aatos Erkko Foundation; the Finnish Diabetes Foundation; the Novo Nordisk Foundation; and the Finnish Cancer Foundation. Our research is also supported by InFLAMES Flagship Programme of the Academy of Finland (decision no.: 337530) and University of Turku Graduate School (UTUGS).

Funding Information:
We thank all voluntary blood donors and personnel of Turku University Hospital, Department of Obstetrics and Gynecology, Maternity Ward (Hospital District of Southwest Finland) for the umbilical cord blood collection. We are grateful to Marjo Hakkarainen and Sarita Heinonen for their excellent technical help. We duly acknowledge Turku Proteomics Facility supported by Biocenter Finland, for their assistance. The Finnish Centre for Scientific Computing (CSC) and ELIXIR Finland are acknowledged for computational resources.

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

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