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2016 ; 113
(50
): 14342-14347
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Multistep regulation of autophagy by WNK1
#MMPMID27911840
Gallolu Kankanamalage S
; Lee AY
; Wichaidit C
; Lorente-Rodriguez A
; Shah AM
; Stippec S
; Whitehurst AW
; Cobb MH
Proc Natl Acad Sci U S A
2016[Dec]; 113
(50
): 14342-14347
PMID27911840
show ga
The with-no-lysine (K) (WNK) kinases are an atypical family of protein kinases
that regulate ion transport across cell membranes. Mutations that result in their
overexpression cause hypertension-related disorders in humans. Of the four
mammalian WNKs, only WNK1 is expressed throughout the body. We report that WNK1
inhibits autophagy, an intracellular degradation pathway implicated in several
human diseases. Using small-interfering RNA-mediated WNK1 knockdown, we show
autophagosome formation and autophagic flux are accelerated. In cells with
reduced WNK1, basal and starvation-induced autophagy is increased. We also show
that depletion of WNK1 stimulates focal class III phosphatidylinositol 3-kinase
complex (PI3KC3) activity, which is required to induce autophagy. Depletion of
WNK1 increases the expression of the PI3KC3 upstream regulator unc-51-like kinase
1 (ULK1), its phosphorylation, and activation of the kinase upstream of ULK1, the
AMP-activated protein kinase. In addition, we show that the N-terminal region of
WNK1 binds to the UV radiation resistance-associated gene (UVRAG) in vitro and
WNK1 partially colocalizes with UVRAG, a component of a PI3KC3 complex. This
colocalization decreases upon starvation of cells. Depletion of the
SPS/STE20-related proline-alanine-rich kinase, a WNK1-activated enzyme, also
induces autophagy in nutrient-replete or -starved conditions, but depletion of
the related kinase and WNK1 substrate, oxidative stress responsive 1, does not.
These results indicate that WNK1 inhibits autophagy by multiple mechanisms.
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