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10.1152/ajprenal.00575.2020 http://scihub22266oqcxt.onion/10.1152/ajprenal.00575.2020 33682442!8174809!33682442     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Am+J+Physiol+Renal+Physiol 2021 ; 320 (5): F734-F747 Nephropedia Template TP {{tp|p=33682442|t=2021. Role of KLHL3 and dietary K(+) in regulating KS-WNK1 expression |pdf=|usr=}}{{33682442}} gab.com Text Role of KLHL3 and dietary K(+) in regulating KS-WNK1 expression JO: Am J Physiol Renal Physiol http://www.kidney.de/pget.php?&tw=1&pmid=33682442 #FOAvip The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH(2)-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K(+) diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K(+) levels.NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K(+) and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3. Twit Text FOAVip Role of KLHL3 and dietary K(+) in regulating KS-WNK1 expression ????Am J Physiol Renal Physiol http://www.kidney.de/pget.php?&tw=1&pmid=33682442 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=33682442 #FOAvip English Wikipedia <ref>{{Cite pmid|33682442}}</ref> Role of KLHL3 and dietary K(+) in regulating KS-WNK1 expression #MMPMID33682442 Ostrosky-Frid M; Chavez-Canales M; Zhang J; Andrukhova O; Argaiz ER; Lerdo-de-Tejada F; Murillo-de-Ozores A; Sanchez-Navarro A; Rojas-Vega L; Bobadilla NA; Vazquez N; Castaneda-Bueno M; Alessi DR; Gamba G Am J Physiol Renal Physiol 2021[May]; 320 (5): F734-F747 PMID33682442show ga The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH(2)-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K(+) diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K(+) levels.NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K(+) and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3. |Adaptor Proteins, Signal Transducing/genetics/*metabolism[MESH] |Animals[MESH] |Cullin Proteins/metabolism[MESH] |Enzyme Stability[MESH] |Female[MESH] |Kidney/*enzymology/physiopathology[MESH] |Mice[MESH] |Mice, Inbred C57BL[MESH] |Mice, Transgenic[MESH] |Microfilament Proteins/genetics/*metabolism[MESH] |Mutation[MESH] |Potassium, Dietary/*metabolism[MESH] |Protein Interaction Domains and Motifs[MESH] |Protein Serine-Threonine Kinases/genetics/metabolism[MESH] |Proteolysis[MESH] |Pseudohypoaldosteronism/*enzymology/genetics/physiopathology[MESH] |Solute Carrier Family 12, Member 3/genetics/metabolism[MESH] |WNK Lysine-Deficient Protein Kinase 1/deficiency/genetics/*metabolism[MESH]Role of KLHL3 and dietary K(+) in regulating KS-WNK1 expression (epmc).pdf DeepDyve Pubget Overpricing