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Glutamine, mTOR inhibition and autophagy

Gastroenterology. 2009 Mar;136(3):924-32. Epub 2008 Dec 3.
 
Glutamine increases autophagy under Basal and stressed conditions in
intestinal epithelial cells.
Sakiyama T, Musch MW, Ropeleski MJ, Tsubouchi H, Chang EB.
Martin Boyer Laboratories, University of Chicago IBD Research Center,
Chicago, Illinois, USA.

BACKGROUND & AIMS: Glutamine plays a protective role in intestinal cells
during physiologic stress; however, the protection mechanisms are not
fully understood. Autophagy functions in bulk degradation of cellular
components, but has been recognized recently as an important mechanism
for cell survival under conditions of stress. We therefore sought to see
if glutamine's actions involve the induction of autophagy in intestinal
cells and, if so, the mechanisms that underlie this action. METHODS:
Formation of microtubule-associated protein light chain 3
(LC3)-phospholipid conjugates (LC3-II) in rat intestinal epithelial
IEC-18 cells and human colonic epithelial Caco-2(BBE) cells was
determined by Western blotting and localized by confocal microscopy.
Activation of mammalian target of rapamycin (mTOR) pathway,
mitogen-activated protein (MAP) kinases, caspase-3, and poly
(ADP-ribose) polymerase were monitored by Western blotting. RESULTS:
Glutamine increased LC3-II as well as the number of autophagosomes.
Glutamine-induced LC3-II formation was paralleled by inactivation of
mTOR and p38 MAP kinase pathways, and inhibition of mTOR and p38 MAP
kinase allowed LC3-II induction in glutamine-deprived cells. Under
glutamine starvation, LC3-II recovery after heat stress or the increase
under oxidative stress was blunted significantly. Glutamine depletion
increased caspase-3 and poly (ADP-ribose) polymerase activity after heat
stress, which was inhibited by treatment with inhibitors of mTOR and p38
MAP kinase. CONCLUSIONS: Glutamine induces autophagy under basal and
stressed conditions, and prevents apoptosis under heat stress through
its regulation of the mTOR and p38 MAP kinase pathways. We propose that
glutamine contributes to cell survival during physiologic stress by
induction of autophagy.

Publication Types:
*  Research Support, N.I.H., Extramural
*  Research Support, Non-U.S. Gov't

PMID: 19121316

Amino Acids. 2009 May;37(1):111-22. Epub 2009 Jan 8.  Related Articles,
LinkOut
 
Glutamine, arginine, and leucine signaling in the intestine.
Marc Rhoads J, Wu G.
Department of Pediatrics, University of Texas Medical School at Houston,
Houston, TX 77030, USA.

Glutamine and leucine are abundant constituents of plant and animal
proteins, whereas the content of arginine in foods and physiological
fluids varies greatly. Besides their role in protein synthesis, these
three amino acids individually activate signaling pathway to promote
protein synthesis and possibly inhibit autophagy-mediated protein
degradation in intestinal epithelial cells. In addition, glutamine and
arginine stimulate the mitogen-activated protein kinase and mammalian
target of rapamycin (mTOR)/p70 (s6) kinase pathways, respectively, to
enhance mucosal cell migration and restitution. Moreover, through the
nitric oxide-dependent cGMP signaling cascade, arginine regulates
multiple physiological events in the intestine that are beneficial for
cell homeostasis and survival. Available evidence from both in vitro and
in vivo animal studies shows that glutamine and arginine promote cell
proliferation and exert differential cytoprotective effects in response
to nutrient deprivation, oxidative injury, stress, and immunological
challenge. Additionally, when nitric oxide is available, leucine
increases the migration of intestinal cells. Therefore, through cellular
signaling mechanisms, arginine, glutamine, and leucine play crucial
roles in intestinal growth, integrity, and function.

Publication Types:
*  Research Support, N.I.H., Extramural
*  Research Support, Non-U.S. Gov't
*  Research Support, U.S. Gov't, Non-P.H.S.
*  Review

PMID: 19130170

Cell. 2009 Feb 6;136(3):521-34.

Comment in:
*  Cell. 2009 Feb 6;136(3):399-400.

Bidirectional transport of amino acids regulates mTOR and autophagy.
Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang
H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK,
Cantley LC, Finan PM, Murphy LO.
Respiratory Diseases Area, Novartis Institutes for BioMedical Research,
Novartis Horsham Research Centre, West Sussex, UK.

Amino acids are required for activation of the mammalian target of
rapamycin (mTOR) kinase which regulates protein translation, cell
growth, and autophagy. Cell surface transporters that allow amino acids
to enter the cell and signal to mTOR are unknown. We show that cellular
uptake of L-glutamine and its subsequent rapid efflux in the presence of
essential amino acids (EAA) is the rate-limiting step that activates
mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5
function inhibits cell growth and activates autophagy. The molecular
basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a
bidirectional transporter that regulates the simultaneous efflux of
L-glutamine out of cells and transport of L-leucine/EAA into cells.
Certain tumor cell lines with high basal cellular levels of L-glutamine
bypass the need for L-glutamine uptake and are primed for mTOR
activation. Thus, L-glutamine flux regulates mTOR, translation and
autophagy to coordinate cell growth and proliferation.

PMID: 19203585

Cell. 2009 Feb 6;136(3):399-400. Related Articles, LinkOut
 
Comment on:
*  Cell. 2009 Feb 6;136(3):521-34.

An amino acid shuffle activates mTORC1.
Cohen A, Hall MN.
Biozentrum, University of Basel, Basel, Switzerland.
The mammalian target of rapamycin complex 1 (mTORC1), which promotes
cell growth, is regulated by specific nutrients such as the amino acid
leucine. In this issue, Nicklin et al. (2009) describe a mechanism by
which glutamine facilitates the uptake of leucine, leading to mTORC1
activation.
Publication Types:
*  Comment

PMID: 19203575

Amino Acids. 2008 Jun;35(1):147-55. Epub 2007 Nov 5.
 
Antagonistic effects of leucine and glutamine on the mTOR pathway in
myogenic C2C12 cells.
Deldicque L, Sanchez Canedo C, Horman S, De Potter I, Bertrand L, Hue L,
Francaux M.
Departement d Education Physique et de Readaptation, Universite
catholique de Louvain, Louvain-la-Neuve, Belgium.

This study compared the effects of leucine and glutamine on the mTOR
pathway, on protein synthesis and on muscle-specific gene expression in
myogenic C(2)C(12) cells. Leucine increased the phosphorylation state of
mTOR, on both Ser2448 and Ser2481, and its downstream effectors,
p70(S6k), S6 and 4E-BP1. By contrast, glutamine decreased the
phosphorylation state of mTOR on Ser2448, p70(S6k) and 4E-BP1, but did
not modify the phosphorylation state of mTOR on Ser2481 and S6. Whilst
the phosphorylation state of the mTOR pathway is usually related to
protein synthesis, the incorporation of labelled methionine/cysteine was
only transiently modified by leucine and was unaltered by glutamine.
However, these two amino acids affected the mRNA levels of desmin,
myogenin and myosin heavy chain in a time-dependant manner. In
conclusion, leucine and glutamine have opposite effects on the mTOR
pathway. Moreover, they induce modification of muscle-specific gene
expression, unrelated to their effects on the mTOR/p70(S6k) pathway.
Publication Types:
*  Comparative Study
*  Research Support, Non-U.S. Gov't

PMID: 17978888

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