Abstract
We reported that kelch-like protein 3 (KLHL3)-Cullin3 E3 ligase ubiquitinates with-no-lysine kinase 4 (WNK4) and that impaired WNK4 ubiquitination causes pseudohypoaldosteronism type II, a hereditary hypertensive disease. However, we also found that KLHL3-induced WNK4 degradation could not be inhibited completely by a proteasome inhibitor. Rather, on exposure, for 24 h, of HEK293T cells expressing WNK4 and KLHL3 to a proteasome inhibitor, epoxomicin, the WNK4 protein level was further decreased. As proteasome inhibition is known to activate p62-mediated selective autophagy, we investigated whether WNK4 degradation induced by KLHL3 is also mediated by such an autophagic mechanism. 3-Methyladenine, an autophagy inhibitor, blocked the epoxomicin-induced decrease in WNK4. Co-immunoprecipitation assays revealed that KLHL3 formed a complex not only with WNK4 but also with p62 via its kelch repeat domain. Under proteasome inhibition, p62 overexpression decreased KLHL3 and WNK4 protein levels, and p62 knockdown dramatically increased KLHL3 and WNK4 protein levels. Based on immunofluorescent staining, transiently overexpressed WNK4 showed punctate localization in the cytoplasm where it co-localized with KLHL3, p62 and light chain 3, a m...Continue Reading
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Citations
Feb 3, 2018·Molecular and Cellular Biochemistry·Woo Young ChungJoo Young Kim
Jan 6, 2017·Molecular and Cellular Biology·Emi SasakiEisei Sohara
Jun 14, 2018·American Journal of Physiology. Renal Physiology·Ryan J CorneliusDavid H Ellison
Aug 28, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Chien-Ming LinShih-Hua Lin
Mar 25, 2016·American Journal of Physiology. Renal Physiology·Hashem A DboukMelanie H Cobb
May 1, 2021·Frontiers in Cardiovascular Medicine·Ya ZhangChong Zhang
Aug 4, 2021·Archives of Biochemistry and Biophysics·Ya ZhangChong Zhang