SCIENCE sciencemag.org
tol 3-phosphate 5-kinase (PIKFYVE), which
is essential for correct processing of mac-
ropinosomes, as well as processing of vacu-
oles involved in digesting bacteria engulfed
by phagocytosis (phagosomes) and recycled
intracellular material (autophagosomes)
( 6 – 9 ). TPCs are not the only channels regu-
lated by PI(3,5)P 2 , and other researchers
have previously shown that PIKFYVE is re-
quired for phagosome maturation in macro-
phages, at least partially through activation
of the lysosomal cation channel mucolipin 1
(TRPML1) ( 6 , 10 ). Whether these two mech-
anisms are complementary or represent cell
type–specific differences is unclear, but the
regulation of vesicle shrinkage via lipid-
gated ion channels appears to be a gen-
eral mechanism. The use of TPCs to drive
macropinosome shrinkage in mammalian
macrophages is likely attributable to the ex-
tremely high sodium concentrations found
in their extracellular fluid. Other channels
may perform a similar role in eukaryotes
living in different ionic environments.
A consequence of the rapid TPC-driven
reduction in lumenal sodium is that water is
also lost from the macropinosome by osmo-
sis. Freeman et al. propose a mechanism by
which the resultant drop in lumenal hydro-
static pressure promotes the tubulation and
recycling of the macropinosome membrane.
They show that BAR domain proteins,
which can sense, stabilize, and sometimes
induce membrane tubulation ( 11 ), are re-
cruited in an osmotically sensitive manner.
Therefore, in the presence of BAR domain–
containing Myc box–dependent interacting
protein 1 (BIN1), osmotic shrinkage facili-
tates the formation of narrow tubules (see
the figure). It remains unclear whether the
BAR domain proteins bind because they
recognize curvature from small shrinkage-
induced wrinkles, or because they respond
to lowering of membrane tension.
Tubulation provides a mechanism to se-
lectively remove and recycle surface proteins
from vesicles while retaining lumenal con-
tents. This is a common mechanism of en-
docytic recycling of membrane constituents
( 11 ). It is particularly important for macropi-
nocytosis, which nonspecifically internalizes
cell surface proteins such as receptors. Main-
taining surface expression of such proteins
is essential for normal cell functions. Surface
proteins are therefore rapidly recycled from
macropinosomes after internalization, pre-
venting their degradation with the rest of
the internalized material ( 12 ). Freeman et al.
show that this recycling is sensitive to TPC-
mediated ion flux.
How general is this mechanism for other
vesicles? Although changes in volume in
other endocytic pathways are smaller, in-
ternalized solvent still needs to be expelled.
Any time a vesicle forms a tubule, propor-
tionally more surface area is used than lu-
menal volume. To maintain hydrostatic
pressure, tubulation must be accompanied
by loss of lumenal content. Given the rela-
tively small volumes that are internalized by
other endocytic pathways and the continued
delivery and retrieval of fluid from early en-
dosomes, considerable shrinkage is unlikely
to be observable. Nonetheless, BAR domain
proteins mediate tubulation and recycling
from nearly all endocytic pathways, implying
that osmosis-mediated shrinkage may be of
general importance. A more general role for
osmotic regulation after clathrin-mediated
endocytosis is also suggested by defects in
recycling of integrins and transferrin recep-
tors in nonmacropinocytic fibroblasts ( 1 ). Al-
though the activity of TPCs is up-regulated
in tissues with high macropinocytic activity,
they are also expressed in cells such as fibro-
blasts where they are found on lysosomes,
which also have high sodium concentrations
( 13 ). It has therefore been proposed that
TPCs regulate lysosomal sodium concentra-
tions to maintain acidification.
It is striking that both TPCs and TRPML1
are regulated by mechanistic target of ra-
pamycin (mTOR) ( 10 , 13 ), a nutrient-sen-
sitive signaling protein that responds to
environmental cues to control cell growth
( 14 ). When nutrients are in abundance,
mTOR phosphorylates TPCs, keeping them
closed, whereas under starvation condi-
tions, channels are constitutively open.
mTOR signaling is frequently dysregulated
in cancer and diabetes, and the cross-talk
between mTOR and TPCs has suggested in-
triguing therapeutic possibilities ( 15 ). Given
the key role of macropinocytosis in feeding
cancer cells, it will be fascinating to explore
how dysregulated mTOR signaling in can-
cer cells affects TPC-mediated macropino-
somal shrinkage. jREFERENCES AND NOTES- S. A. Freeman et al., Science 367 , 301 (2020).
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- R. M. Dayam et al., Tr a f f i c 16 , 1010 (2015).
- J. de Lartigue et al., Tr a f f i c 10 , 883 (2009).
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ACKNOWLEDGMENTS
J.S.K. is supported by a Royal Society Fellowship.
10.1126/science aba3623By Chrysothemis Brown1,2
and Alexander Y. Rudensky1,2T
he adaptive immune system, with
T and B lymphocytes being its two
principal cell types, enables efficient
protection from countless pathogens.
T lymphocytes emerge from the thy-
mus as quiescent (noncycling) naïve
cells and display an immense repertoire of
clonally distributed T cell receptors (TCRs)
that detect antigens and are generated as
the result of a largely random process of
somatic gene rearrangement in thymic
precursor cells. On page 264 of this issue,
ElTanbouly et al. ( 1 ) show that naïve T cell
quiescence is actively regulated upon their
egress from the thymus and that this maybe critical for constraining self-reactive
T cells and preventing autoimmunity.
TCRs recognize antigens in the form of
peptide fragments, bound to major histo-
compatibility complex (MHC) molecules.
These peptides are generated intracellu-
larly either from proteins of foreign origin,
including pathogens, or from endogenous
“self ” proteins. During thymic differen-
tiation, an intricate selection process elimi-
nates naïve T cells with a strong affinity for
self-peptide–MHC complexes. Upon egress
from the thymus, these T cells, identified by
low expression of the cell adhesion molecule
CD44 and high expression of the lymph
node homing receptor CD62L, continue to
survey peptide-MHC complexes displayed
on the surface of antigen-presenting cells.IMMUNOLOGYEnforcing T cell
innocence
Inhibitory signaling on
T cells maintains “naïvety”
to self-antigen
(^1) Howard Hughes Medical Institute and Immunology
Program, Sloan Kettering Institute, New York, NY 10065,
USA.^2 Ludwig Center, Memorial Sloan Kettering Cancer
Center, New York, NY 10065, USA.
Email: [email protected]; [email protected]
“...naïve T cell quiescence is
actively maintained to prevent
inappropriate activation
and ensuing autoimmunity.”
17 JANUARY 2020 • VOL 367 ISSUE 6475 247
Published by AAAS