The underlying mechanism of proinflammatory NF-κB activation by the mTORC2/Akt/IKKα pathway during skin aging.

Yeon Ja Choi,Daeui Park,Ki Wung Chung,Ji Won Jeong,Hae Young Chung,Dae Hyun Kim,Kyoung Mi Moon,Byung Pal Yu

doi:10.18632/oncotarget.10943

Abstract

Mammalian target of rapamycin complex 2 (mTORC2), one of two different enzymatic complexes of mTOR, regulates a diverse set of substrates including Akt. mTOR pathway is one of well-known mediators of aging process, however, its role in skin aging has not been determined. Skin aging can be induced by physical age and ultraviolet (UV) irradiation which are intrinsic and extrinsic factors, respectively. Here, we report increased mTORC2 pathway in intrinsic and photo-induced skin aging, which is implicated in the activation of nuclear factor-κB (NF-κB). UVB-irradiated or aged mice skin revealed that mTORC2 activity and its component, rictor were significantly upregulated which in turn increased Akt activation and Akt-dependent IκB kinase α (IKKα) phosphorylation at Thr23 in vivo. We also confirmed that UVB induced the mTORC2/Akt/IKKα signaling pathway with HaCaT human normal keratinocytes. The increased mTORC2 signaling pathway during skin aging were associated to NF-κB activation. Suppression of mTORC2 activity by the treatment of a mTOR small inhibitor or knockdown of RICTOR partially rescued UVB-induced NF-κB activation through the downregulation of Akt/IKKα activity. Our data demonstrated the upregulation of mTORC2 pathway in intrinsic and photo-induced skin aging and its role in IKKα/NF-κB activation. These data not only expanded the functions of mTOR to skin aging but also revealed the therapeutic potential of inhibiting mTORC2 in ameliorating both intrinsic skin aging and photoaging.

Highlights

Mammalian target of rapamycin is an evolutionarily conserved nutrient-sensing protein kinase that belongs to the PI3K-related kinase family
MTOR forms two different enzymatic complexes, Mammalian target of rapamycin (mTOR) complexes 1 and 2, that possess distinct functions and components [4]. Mammalian target of rapamycin complex 2 (mTORC2) consists of mTOR, G-protein β-subunit-like protein (GβL, known as mammalian lethal with sec-13 protein 8), rapamycin-insensitive companion of mTOR (Rictor), stress-activated protein kinase interacting protein 1 (Sin1) and protein observed with Rictor (Protor)-1 or Protor-2. mTORC2 has been www.impactjournals.com/oncotarget identified as the critical upstream kinase responsible for the phosphorylation of Akt at Ser473 and its activation [5]
The current study demonstrates the upregulation of mTORC2 signaling pathway and its role in skin aging

Summary

Introduction

Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient-sensing protein kinase that belongs to the PI3K-related kinase family. The mTOR signaling pathway has attracted considerable attention in the field of aging research because its suppression was found to extend the lifespan of various organisms [1, 2]. There is no study to date that examined the function of mTOR signaling pathway in skin aging. Ultraviolet (UV) irradiation is the most powerful and common environmental factor accelerating skin aging, commonly referred to as photoaging [3]. MTORC2 consists of mTOR, G-protein β-subunit-like protein (GβL, known as mammalian lethal with sec-13 protein 8), rapamycin-insensitive companion of mTOR (Rictor), stress-activated protein kinase interacting protein 1 (Sin1) and protein observed with Rictor (Protor)-1 or Protor-2. MTORC2 has been www.impactjournals.com/oncotarget identified as the critical upstream kinase responsible for the phosphorylation of Akt at Ser473 and its activation [5]. MTORC2 has a great potential to modulate various substrates that are known to be regulated by Akt

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