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.

Keywords: AMPK; OSR1; PI3KC3; SPAK; ULK1; UVRAG; Vps34; with no lysine.

Figure 1.

The model of how WNK1 regulates autophagy. WNK1 inhibits autophagy by multiple mechanisms. It directly binds UVRAG and inhibits the action of the PtdIns3K complex on autophagosome maturation. In addition, WNK1 inhibits the expression of ULK1. Moreover, WNK1 inhibits the activation of AMPK and, subsequently, AMPK-dependent pro-autophagic phosphorylation of ULK1 at Ser555. This figure has been modified from Fig. 5F of Gallolu Kankanamalage, S., et al., Proc Natl Acad Sci USA, 2016; 113:14342–7. © National Academy of the Sciences. Reproduced by permission of National Academy of the Sciences. Permission to reuse must be obtained from the rightsholder.