PMID- 24282297
OWN - NLM
STAT- MEDLINE
DCOM- 20140221
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 50
DP  - 2013 Dec 10
TI  - Tuberous sclerosis 1 (Tsc1)-dependent metabolic checkpoint controls development 
      of dendritic cells.
PG  - E4894-903
LID - 10.1073/pnas.1308905110 [doi]
AB  - Coordination of cell metabolism and immune signals is crucial for lymphocyte 
      priming. Emerging evidence also highlights the importance of cell metabolism for 
      the activation of innate immunity upon pathogen challenge, but there is little 
      evidence of how this process contributes to immune cell development. Here we show 
      that differentiation of dendritic cells (DCs) from bone marrow precursors is 
      associated with dynamic regulation of mechanistic target of rapamycin (mTOR) 
      complex 1 (mTORC1) signaling and cell metabolism. Unexpectedly, enhancing mTORC1 
      activity via ablation of its negative regulator tuberous sclerosis 1 (Tsc1) 
      impaired DC development in vivo and in vitro, associated with defective cell 
      survival and proliferation. Moreover, Tsc1 deficiency caused DC spontaneous 
      maturation but a propensity to differentiate into other lineages, and attenuated 
      DC-mediated effector TH1 responses. Mechanistically, Tsc1-deficient DCs exhibited 
      increased glycolysis, mitochondrial respiration, and lipid synthesis that were 
      partly mediated by the transcription factor Myc, highlighting a key role of Tsc1 
      in modulating metabolic programming of DC differentiation. Further, Tsc1 signaled 
      through Rheb to down-regulate mTORC1 for proper DC development, whereas its 
      effect at modulating mTOR complex 2 (mTORC2) activity was largely dispensable. 
      Our results demonstrate that the interplay between Tsc1-Rheb-mTORC1 signaling and 
      Myc-dependent bioenergetic and biosynthetic activities constitutes a key 
      metabolic checkpoint to orchestrate DC development.
FAU - Wang, Yanyan
AU  - Wang Y
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 
      38105.
FAU - Huang, Gonghua
AU  - Huang G
FAU - Zeng, Hu
AU  - Zeng H
FAU - Yang, Kai
AU  - Yang K
FAU - Lamb, Richard F
AU  - Lamb RF
FAU - Chi, Hongbo
AU  - Chi H
LA  - eng
GR  - R01 AI101407/AI/NIAID NIH HHS/United States
GR  - R01 NS064599/NS/NINDS NIH HHS/United States
GR  - R21 AI094089/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131126
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Tsc1 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tumor Suppressor Proteins)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Dendritic Cells/*immunology
MH  - Energy Metabolism/immunology
MH  - Flow Cytometry
MH  - Lymphocyte Activation/*immunology
MH  - Metabolic Networks and Pathways/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Real-Time Polymerase Chain Reaction
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tumor Suppressor Proteins/immunology/*metabolism
PMC - PMC3864282
COIS- The authors declare no conflict of interest.
EDAT- 2013/11/28 06:00
MHDA- 2014/02/22 06:00
PMCR- 2014/06/10
CRDT- 2013/11/28 06:00
PHST- 2013/11/28 06:00 [entrez]
PHST- 2013/11/28 06:00 [pubmed]
PHST- 2014/02/22 06:00 [medline]
PHST- 2014/06/10 00:00 [pmc-release]
AID - 1308905110 [pii]
AID - 201308905 [pii]
AID - 10.1073/pnas.1308905110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):E4894-903. doi: 
      10.1073/pnas.1308905110. Epub 2013 Nov 26.