Angiotensin II type-1 receptor-associated protein interacts with transferrin receptor-1 and promotes its internalization.

Scientific reports 2022 Oct 17

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Kidney fibrosis is a common pathway that leads to chronic kidney disease. Angiotensin II type-1 receptor (AT1R)-associated protein (ATRAP) was originally identified as an AT1R-binding protein. Previously, we reported that systemic knockout of ATRAP exacerbates kidney fibrosis in aged mice. Although these effects of ATRAP appeared to be AT1R-independent actions, the molecular mechanism remains poorly understood. To elucidate the molecular mechanism of ATRAP independent of AT1R, we explored novel ATRAP-interacting proteins. Mass spectrometric analysis of the immunoprecipitants of a Flag-tagged ATRAP complex revealed 376 candidate proteins that potentially interact with ATRAP. Gene ontology analysis revealed that proteins related to vesicle trafficking, membrane transport, and many membrane proteins, including transferrin receptor 1 (TfR1), were enriched. Because TfR1 promotes cellular iron uptake and iron is a key factor involved in kidney fibrosis, we focused on TfR1 and confirmed that it interacts with ATRAP. In addition, our findings revealed that enhanced ATRAP expression decreased cell-surface TfR1 expression without altering the overall cellular TfR1 expression levels. Furthermore, enhanced ATRAP expression attenuated cellular iron levels. Together, our results highlight the role of ATRAP as a suppressor of TfR1 that functions by facilitating TfR1 internalization, which affects iron metabolism and oxidative stress signaling. © 2022. The Author(s).

Citation

Eriko Abe, Akio Yamashita, Keigo Hirota, Takahiro Yamaji, Kengo Azushima, Shingo Urate, Toru Suzuki, Shohei Tanaka, Shinya Taguchi, Shunichiro Tsukamoto, Tatsuki Uehara, Hiromichi Wakui, Kouichi Tamura, Hidehisa Takahashi. Angiotensin II type-1 receptor-associated protein interacts with transferrin receptor-1 and promotes its internalization. Scientific reports. 2022 Oct 17;12(1):17376