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The complex of Fas-associated factor 1 with Hsp70 stabilizes the adherens junction integrity by suppressing RhoA activation
Soonhwa Song1,† , Joon Kyu Park2,† , Sang Chul Shin2,3,† , Jae-Jin Lee1 , Seung Kon Hong2 , In-Kang Song1 , Bokyung Kim1 , Eun Joo Song1,* , Kong-Joo Lee1,* , Eunice EunKyeong Kim2,*
1Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
2Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
3Present address: Technology Support Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
These authors contributed equally to this work.
*Correspondence to:Eun Joo Song , Kong-Joo Lee , Eunice EunKyeong Kim ,
J Mol Cell Biol, Volume 14, Issue 6, June 2022, mjac037,
Keyword: human Fas-associated factor 1 (FAF1), heat shock protein 70 (Hsp70), adherens junction, RhoA activation, IQGAP1, X-ray crystallography, FAF1–Hsp70 complex

Fas-associated factor 1 (FAF1) is a scaffolding protein that plays multiple functions, and dysregulation of FAF1 is associated with many types of diseases such as cancers. FAF1 contains multiple ubiquitin-related domains (UBA, UBL1, UBL2, UAS, and UBX), each domain interacting with a specific partner. In particular, the interaction of UBL1 with heat shock protein 70 (Hsp70) is associated with tumor formation, although the molecular understanding remains unknown. In this study, the structural analysis revealed that His160 of FAF1 is important for its interaction with Hsp70. The association of Hsp70 with FAF1 is required for the interaction with IQGAP1. FAF1 negatively regulates RhoA activation by FAF1–Hsp70 complex formation, which then interacts with IQGAP1. These steps play a key role in maintaining the stability of cell-to-cell junction. We conclude that FAF1 plays a critical role in the structure and function of adherens junction during tissue homeostasis and morphogenesis by suppressing RhoA activation, which induces the activation of Rho-associated protein kinase, phosphorylation of myosin light chain, formation of actin stress fiber, and disruption of adherens junction. In addition, depletion of FAF1 increased collective invasion in a 3D spheroid cell culture. These results provide insight into how the FAF1–Hsp70 complex acts as a novel regulator of the adherens junction integrity. The complex can be a potential therapeutic target to inhibit tumorigenesis and metastasis.