title: WNK1 is an unexpected autophagy inhibitor.
abstract: Autophagy is a cellular degradation pathway that is essential to maintain cellular physiology, and deregulation of autophagy leads to multiple diseases in humans. In a recent study, we discovered that the protein kinase WNK1 (WNK lysine deficient protein kinase 1) is an inhibitor of autophagy. The loss of WNK1 increases both basal and starvation-induced autophagy. In addition, the depletion of WNK1 increases the activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, which is required to induce autophagy. Moreover, the loss of WNK1 increases the expression of ULK1 (unc-51 like kinase 1), which is upstream of the PtdIns3K complex. It also increases the pro-autophagic phosphorylation of ULK1 at Ser555 and the activation of AMPK (AMP-activated protein kinase), which is responsible for that phosphorylation. The inhibition of AMPK by compound C decreases the magnitude of autophagy induction following WNK1 loss; however, it does not prevent autophagy induction. We found that the UVRAG (UV radiation resistance associated gene), which is a component of the PtdIns3K, binds to the N-terminal region of WNK1. Moreover, WNK1 partially colocalizes with UVRAG and this colocalization decreases when autophagy is stimulated in cells. The loss of WNK1 also alters the cellular distribution of UVRAG. The depletion of the downstream target of WNK1, OXSR1/OSR1 (oxidative-stress responsive 1) has no effect on autophagy, whereas the depletion of its relative STK39/SPAK (serine/threonine kinase 39) induces autophagy under nutrient-rich and starved conditions.
authors.affiliation: a Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Sachith
authors.initials: S
authors.lastname: Gallolu Kankanamalage
authors.affiliation: a Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: A-Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: a Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Chonlarat
authors.initials: C
authors.lastname: Wichaidit
authors.affiliation: a Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Lorente-Rodriguez
authors.affiliation: a Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Akansha M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: a Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Stippec
authors.affiliation: b Harold C. Simmons Comprehensive Cancer Center , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Angelique W
authors.initials: AW
authors.lastname: Whitehurst
authors.affiliation: a Department of Pharmacology , University of Texas Southwestern Medical Center , Dallas , TX , USA.|b Harold C. Simmons Comprehensive Cancer Center , University of Texas Southwestern Medical Center , Dallas , TX , USA.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1 / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; D055372:AMP-Activated Protein Kinases
keywords: AMPK; OSR1; PI3KC3; SPAK; ULK1; UVRAG; Vps34; with no lysine