Macroautophagy Regulates Energy Metabolism during Effector T Cell Activation

Hubbard, Vanessa M.; Valdor, Rut; Patel, Bindi; Singh, Rajat; Cuervo, Ana María; Macian, Fernando

doi:10.4049/jimmunol.1000576

Cited by 242 publications

(299 citation statements)

References 63 publications

(78 reference statements)

Supporting

Mentioning

279

Contrasting

Unclassified

Order By: Relevance

“…It also maintains the calcium flux and the pro-survival process and counteracts pro-apoptotic action to maintain T-cell homeostasis [42][43][44][45] . Cyt1 induces autophagosome formation when it binds to CD46, which may function in maintaining the homeostasis of T-cells during adaptive immunity [46] .…”

Section: Autoreactive T-cell Regulation By Autophagymentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

View full text Add to dashboard Cite

Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

show abstract

Section: Autoreactive T-cell Regulation By Autophagymentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

View full text Add to dashboard Cite

show abstract

“…5,6 Autophagy plays an essential role in the development and function of T lymphocytes. Autophagy regulates the calcium mobilization and energy metabolism in T cells, [7][8][9] is critical for effector CD8 + T cell survival and memory formation, 10,11 promotes the proliferation and survival of invariant NKT cells 12,13 and tunes down TCR signaling by degrading BCL10. 14 Autophagy starts with a membrane precursor called the phagophore.…”

Section: Introductionmentioning

confidence: 99%

Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1

Jia

McLeod

et al. 2015

Autophagy

View full text Add to dashboard Cite

The highly conserved cellular degradation pathway, macroautophagy, regulates the homeostasis of organelles and promotes the survival of T lymphocytes. Previous results indicate that Atg3-, Atg5-, or Pik3c3/Vps34-deficient T cells cannot proliferate efficiently. Here we demonstrate that the proliferation of Atg7-deficient T cells is defective. By using an adoptive transfer and Listeria monocytogenes (LM) mouse infection model, we found that the primary immune response against LM is intrinsically impaired in autophagy-deficient CD8 + T cells because the cell population cannot expand after infection. Autophagy-deficient T cells fail to enter into S-phase after TCR stimulation. The major negative regulator of the cell cycle in T lymphocytes, CDKN1B, is accumulated in autophagy-deficient na€ ıve T cells and CDKN1B cannot be degraded after TCR stimulation. Furthermore, our results indicate that genetic deletion of one allele of CDKN1B in autophagy-deficient T cells restores proliferative capability and the cells can enter into S-phase after TCR stimulation. Finally, we found that natural CDKN1B forms polymers and is physiologically associated with the autophagy receptor protein SQSTM1/p62 (sequestosome 1). Collectively, autophagy is required for maintaining the expression level of CDKN1B in na€ ıve T cells and selectively degrades CDKN1B after TCR stimulation.

show abstract

“…En effet, Schuster et ses collègues ont montré que le gène Clec16A, orthologue murin d'un [10]. Plusieurs éléments justifient le rôle de l'autophagie dans l'activation des LT. Tout d'abord, elle permet à la cellule de répondre à la demande d'énergie qui résulte de la stimulation du TCR [24]. En réduisant le nombre de mitochondries non fonctionnelles, elle prévient de plus l'accumulation de ROS qui favorise l'apoptose [11,12].…”

Section: Autophagie Et éDucation Des Lymphocytes Tunclassified

“…On peut donc penser qu'en absence d'autophagie les défauts de prolifération et de survie observés en réponse à une stimulation du TCR, sont en partie dus à l'expansion du réticu-lum endoplasmique (RE) [22,23] et de la masse mitochondriale [11,12]. L'autophagie permet également de soutenir la demande métabolique en générant des acides aminés (AA) [24]. Enfin, elle permet de dégrader les pro-caspases [25].…”

Section: Le Rôle De L'autophagie Dans La Survie Et L'activation Des Lunclassified