effects of PD-1 blockade in cancer and
chronic viral infection (Chen et al., 2015;
Zelenay et al., 2015). Furthermore, metal-
lothionein expression can be enhanced
by adenosine (Xiong et al., 1992) and
cAMP/PKA signaling, providing another
link between these pathways in lympho-
cyte dysfunction.
Lastly, it will be important to link the
dysfunctional gene program(s) to T cell
metabolism because decreased glycol-
ysis and mitochondrial function are core
to T cell dysfunction (Chang and Pearce,
2016 ). PD-1 can suppress T cell glycol-
ysis, and conversely, increasing hypoxia
inducible factor-1 alpha (HIF-1a) activity
boosts glycolysis as well as effector func-
tions in CD8 T cells in chronic viral infec-
tion and tumors (Doedens et al., 2013).
Perhaps, HIF-1acounteracts GATA3 and
IKZF2 to promote ‘‘activation’’ gene
expression and metabolic states optimal
for CD8 T cell effector function. In relation,
hypoxic stress can paradoxically increase
production of reactive oxygen species
and possibly infiltrating lymphocytes
combat this in hypoxic tumor microenvi-
ronments by importing Zn2+as an antiox-
idant. However, this in turn, may increase
metallothionein expression and further
suppress T cell function and mitochon-
drial respiration. Thus, while signaling
through co-inhibitory receptors may set
the stage for T cell dysfunction, the even-
tual loss of bioenergetic potential and al-
terations of intracellular metabolites and
ions may ultimately remodel the transcrip-
tional and epigenetic landscape that man-
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at the Nuclear Pore Complex
Mary Dasso1,and Beatriz M.A. Fontoura2,
(^1) Division of Molecular and Cellular Biology, National Institute of Child Health and Human Development, National Institutes of Health,
Bethesda, MD 20892, USA
(^2) Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
*Correspondence:[email protected](M.D.),[email protected](B.M.A.F.)
http://dx.doi.org/10.1016/j.cell.2016.08.026
The nuclear pore complex is the primary conduit for nuclear import and export of molecules. In this
issue, Gu et al. uncover a novel mechanism in which immune signaling and programmed cell death
require nuclear pore rearrangement and release of sequestered cyclin-dependent kinase inhibitors
to elicit immunity and death.
Trafficking of molecules in and out of the
nucleus occurs through nuclear pore
complexes (NPCs). NPCs are composed
of proteins called nucleoporins that main-
tain NPC structure and/or mediate nucle-
ocytoplasmic trafficking. Translocation of
large cargos through NPCs requires regu-
lated interactions between cargo-bound
transport receptors and nucleoporins.
Throughout evolution, components of
the nuclear transport machinery have
been targets of pathogens as well as
important components of immune re-
sponses. Certain nucleoporins and nu-
clear transport factors interact with
pathogenic factors and mediate specific
immune responses in both mammals
(Faria et al., 2006; Yarbrough et al.,
2014 ) and plants (Cheng et al., 2009;
Palma et al., 2005; Zhang and Li, 2005).
In plants, a diverse set of nucleotide-bind-
ing leucine-rich repeat receptor proteins
(NB-LRRs) are activated in response to
pathogens, thereby promoting effector-
triggered immunity (ETI) and ETI-associ-
ated programmed cell death (PCD). Plant
cells with a gain-of-function mutation in a
1364 Cell 166 , September 8, 2016ª2016 Elsevier Inc.