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Evidence for Urate Uptake Through Monocarboxylate Transporter 9 Expressed in Mammalian Cells and Its Enhancement by Heat Shock

Naoyuki Otani, Yasutaka Kurata, Nani Maharani, Masanari Kuwabara, Nobuhito Ikeda, Tomomi Notsu, Peili Li, Junichiro Miake, Akio Yoshida, Hiromi Sakaguchi, Katsumi Higaki, Naoe Nakasone, Motokazu Tsuneto, Yasuaki Shirayoshi, Motoshi Ouchi, Haruaki Ninomiya, Kazuhiro Yamamoto, Naohiko Anzai, Ichiro Hisatome
Published: 7 August 2020
Circulation Reports , Volume 2, pp 425-432; doi:10.1253/circrep.cr-20-0016

Abstract: Background:Monocarboxylate transporter 9 (MCT9), an orphan transporter member of the solute carrier family 16 (SLC16), possibly reabsorbs uric acid in the renal tubule and has been suggested by genome-wide association studies to be involved in the development of hyperuricemia and gout. In this study we investigated the mechanisms regulating the expression of human (h) MCT9, its degradation, and physiological functions. Methods and Results:hMCT9-FLAG was stably expressed in HEK293 cells and its degradation, intracellular localization, and urate uptake activities were assessed by pulse-chase analysis, immunofluorescence, and [14C]-urate uptake experiments, respectively. hMCT9-FLAG was localized on the plasma membrane as well as in the endoplasmic reticulum and Golgi apparatus. The proteasome inhibitors MG132 and lactacystine increased levels of hMCT9-FLAG protein expression with enhanced ubiquitination, prolonged their half-life, and decreased [14C]-urate uptake. [14C]-urate uptake was increased by both heat shock (HS) and the HS protein inducer geranylgeranylacetone (GGA). Both HS and GGA restored the [14C]-urate uptake impaired by MG132. Conclusions:hMCT9 does transport urate and is degraded by a proteasome, inhibition of which reduces hMCT9 expression on the cell membrane and urate uptake. HS enhanced urate uptake through hMCT9.
Keywords: Protein / Transporter / heat shock / Gga / Monocarboxylate / Urate Uptake

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