Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema.
Rtp801 (also known as Redd1, and encoded by Ddit4), a stress-related protein triggered by adverse environmental conditions, inhibits mammalian target of rapamycin (mTOR) by stabilizing the TSC1-TSC2 inhibitory complex and enhances oxidative stress-dependent cell death. We postulated that Rtp801 acts as a potential amplifying switch in the development of cigarette smoke-induced lung injury, leading to emphysema. Rtp801 mRNA and protein were overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The regulation of Rtp801 expression by cigarette smoke may rely on oxidative stress-dependent activation of the CCAAT response element in its promoter. We also found that Rtp801 was necessary and sufficient for nuclear factor-kappaB (NF-kappaB) activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF-kappaB activation, alveolar inflammation, oxidative stress and apoptosis of alveolar septal cells. In contrast, Rtp801 knockout mice were markedly protected against acute cigarette smoke-induced lung injury, partly via increased mTOR signaling, and, when exposed chronically to cigarette smoke, against emphysema. Our data support the notion that Rtp801 may represent a major molecular sensor and mediator of cigarette smoke-induced lung injury.
Yoshida
Toshinori
T
Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Mett
Igor
I
Bhunia
Anil K
AK
Bowman
Joel
J
Perez
Mario
M
Zhang
Li
L
Gandjeva
Aneta
A
Zhen
Lijie
L
Chukwueke
Ugonma
U
Mao
Tianzhi
T
Richter
Amy
A
Brown
Emile
E
Ashush
Hagit
H
Notkin
Natalie
N
Gelfand
Anna
A
Thimmulappa
Rajesh K
RK
Rangasamy
Tirumalai
T
Sussan
Thomas
T
Cosgrove
Gregory
G
Mouded
Majd
M
Shapiro
Steven D
SD
Petrache
Irina
I
Biswal
Shyam
S
Feinstein
Elena
E
Tuder
Rubin M
RM
D000818:Animals; D004789:Enzyme Activation; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008168:Lung / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011650:Pulmonary Alveoli / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
C469991:DDIT4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014157:Transcription Factors; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
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