PMID- 36987917
OWN - NLM
STAT- MEDLINE
DCOM- 20230606
LR  - 20230613
IS  - 1469-3178 (Electronic)
IS  - 1469-221X (Print)
IS  - 1469-221X (Linking)
VI  - 24
IP  - 6
DP  - 2023 Jun 5
TI  - Resting natural killer cell homeostasis relies on tryptophan/NAD(+) metabolism 
      and HIF-1alpha.
PG  - e56156
LID - 10.15252/embr.202256156 [doi]
LID - e56156
AB  - Natural killer (NK) cells are forced to cope with different oxygen environments 
      even under resting conditions. The adaptation to low oxygen is regulated by 
      oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The 
      function of HIFs for NK cell activation and metabolic rewiring remains 
      controversial. Activated NK cells are predominantly glycolytic, but the metabolic 
      programs that ensure the maintenance of resting NK cells are enigmatic. By 
      combining in situ metabolomic and transcriptomic analyses in resting murine NK 
      cells, our study defines HIF-1alpha as a regulator of tryptophan metabolism and 
      cellular nicotinamide adenine dinucleotide (NAD(+) ) levels. The HIF-1alpha/NAD(+) 
      axis prevents ROS production during oxidative phosphorylation (OxPhos) and 
      thereby blocks DNA damage and NK cell apoptosis under steady-state conditions. In 
      contrast, in activated NK cells under hypoxia, HIF-1alpha is required for glycolysis, 
      and forced HIF-1alpha expression boosts glycolysis and NK cell performance in vitro 
      and in vivo. Our data highlight two distinct pathways by which HIF-1alpha interferes 
      with NK cell metabolism. While HIF-1alpha-driven glycolysis is essential for NK cell 
      activation, resting NK cell homeostasis relies on HIF-1alpha-dependent 
      tryptophan/NAD(+) metabolism.
CI  - (c) 2023 The Authors. Published under the terms of the CC BY 4.0 license.
FAU - Pelletier, Abigaelle
AU  - Pelletier A
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Nelius, Eric
AU  - Nelius E
AUID- ORCID: 0000-0002-9689-6926
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Fan, Zheng
AU  - Fan Z
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Khatchatourova, Ekaterina
AU  - Khatchatourova E
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Alvarado-Diaz, Abdiel
AU  - Alvarado-Diaz A
AUID- ORCID: 0000-0003-3678-7143
AD  - Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
FAU - He, Jingyi
AU  - He J
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Krzywinska, Ewelina
AU  - Krzywinska E
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Sobecki, Michal
AU  - Sobecki M
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Nagarajan, Shunmugam
AU  - Nagarajan S
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
FAU - Kerdiles, Yann
AU  - Kerdiles Y
AD  - Centre d'Immunologie de Marseille-Luminy, Aix Marseille Universite UM2, Inserm, 
      U1104, CNRS UMR7280, Marseille, France.
FAU - Fandrey, Joachim
AU  - Fandrey J
AD  - Institut fur Physiologie, Universitatsklinikum Essen, Universitat Duisburg-Essen, 
      Essen, Germany.
FAU - Gotthardt, Dagmar
AU  - Gotthardt D
AUID- ORCID: 0000-0002-8416-1236
AD  - Institute of Pharmacology and Toxicology, University of Veterinary Medicine, 
      Vienna, Austria.
FAU - Sexl, Veronika
AU  - Sexl V
AD  - University of Innsbruck, InnSbruck, Austria.
FAU - de Bock, Katrien
AU  - de Bock K
AD  - Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
FAU - Stockmann, Christian
AU  - Stockmann C
AUID- ORCID: 0000-0002-9726-6838
AD  - Institute of Anatomy, University of Zurich, Zurich, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230329
PL  - England
TA  - EMBO Rep
JT  - EMBO reports
JID - 100963049
RN  - 8DUH1N11BX (Tryptophan)
RN  - 0U46U6E8UK (NAD)
RN  - S88TT14065 (Oxygen)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Tryptophan/metabolism
MH  - *NAD
MH  - Killer Cells, Natural
MH  - Glycolysis/genetics
MH  - Hypoxia/metabolism
MH  - Cell Hypoxia
MH  - Oxygen/metabolism
MH  - Homeostasis
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism
PMC - PMC10240188
OTO - NOTNLM
OT  - HIF
OT  - immunometabolism
OT  - natural killer cells
OT  - nicotinamide adenine dinucleotide
OT  - tryptophan
COIS- The authors declare that they have no conflict of interest.
EDAT- 2023/03/30 06:00
MHDA- 2023/06/06 06:42
PMCR- 2023/03/29
CRDT- 2023/03/29 05:03
PHST- 2023/03/05 00:00 [revised]
PHST- 2022/09/20 00:00 [received]
PHST- 2023/03/10 00:00 [accepted]
PHST- 2023/06/06 06:42 [medline]
PHST- 2023/03/30 06:00 [pubmed]
PHST- 2023/03/29 05:03 [entrez]
PHST- 2023/03/29 00:00 [pmc-release]
AID - EMBR202256156 [pii]
AID - 10.15252/embr.202256156 [doi]
PST - ppublish
SO  - EMBO Rep. 2023 Jun 5;24(6):e56156. doi: 10.15252/embr.202256156. Epub 2023 Mar 
      29.