SGK1 Inhibits Autophagy in Murine Muscle Tissue

Abstract

Background/Aims As autophagy is linked to several pathological conditions, like cancer and neurodegenerative diseases, it is crucial to understand its regulatory signaling network. In this study, we investigated the role of the serum- and glucocorticoid-induced protein kinase 1 (SGK1) in the control of autophagy. Methods To measure autophagic activity in vivo, we quantified the abundance of the autophagy conjugates LC3-PE (phosphatidylethanolamine) and ATG12-ATG5 in tissue extracts of SGK1 wild-type (Sgk1 +/+) and knockout (Sgk1 −/−) mice that were either fed or starved for 24 h prior sacrifice. In vitro, we targeted SGK1 by RNAi using GFP-WIPI1 expressing U-2 OS cells to quantify the numbers of cells displaying newly formed autophagosomes. In parallel, these cells were also assessed with regard to LC3 and ULK1 by quantitative Western blotting. Results The abundance of both LC3-PE (LC3-II) and ATG12-ATG5 was significantly increased in red muscle tissues of SGK1 knockout mice. This was found in particular in fed conditions, suggesting that SGK1 may keep basal autophagy under control in red muscle in vivo. Under starved conditions, significant differences were observed in SGK1-deficient white muscle tissue and, under fed conditions, also in the liver. In vitro, we found that SGK1 silencing provoked a significant increase of cells displaying WIPI1-positive autophagosomes and autophagosomal LC3 (LC3-II). Moreover, autophagic flux assessments revealed that autophagic degradation significantly increased in the absence of SGK1, strongly suggesting that SGK1 inhibits both autophagosome formation and autophagic degradation in vitro. In addition, more ULK1 protein lacking the inhibitory, TORC1-specific phosphorylation at serine 758 was detected in the absence of SGK1. Conclusions Combined, our data strongly support the idea that SGK1 inhibits the process of autophagy. Mechanistically, our data suggest that SGK1 should act upstream of ULK1 in regulating autophagy, and we hypothesize that SGK1 contributes to the regulation of ULK1 gene expression.

Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

“…Serum‐ and glucocorticoid‐regulated kinase 1 is a powerful regulator of autophagy , and we also confirmed that SGK1 regulates autophagy in chondrocytes. Since IL‐1β inhibits autophagy in chondrocytes , SGK1 knockdown significantly increased the levels of autophagy‐related proteins, including LC3‐II and Beclin‐1, which were decreased by IL‐1β stimulation.…”

“…Based on accumulating evidence, SGK1 is a negative regulator of autophagy [22,23], and the inhibition of SGK1 by SI113 increases the LC3-I/ LC3-II conversion and Beclin-1 levels in human glioblastoma cells [24]. More recently, autophagy levels were reported to be significantly increased in the muscle tissues from sgk1 knockout mice compared to the levels in wild-type mice [25]. These studies strongly support the hypothesis that SGK1 is a negative regulator of autophagy; however, the effect of SGK1 on OA disease development has not been defined.…”

Cutaneous and hepatic vascular lesions due to a recurrent somatic GJA4 mutation reveal a pathway for vascular malformation

“…These findings are consistent with evidence shown by others demonstrating that SGK1 inhibits autophagy. 79 , 80 Whether this autophagic block contributes to HH development is unknown. However, autophagy inhibition can lead to increased cell proliferation in vivo , as has been demonstrated in colorectal cancer cells.…”

Intracarotid cold saline infusion contributes to neuroprotection in MCAO‑induced ischemic stroke in rats via serum and glucocorticoid‑regulated kinase 1

“…channel expression, as well as in promoting proliferation and survival in malignant epithelial cells (12). recently, several studies have confirmed that SGK1 has a protective effect on ischemia-reperfusion injury.…”