INSIGHTS | PERSPECTIVES
32 2 JANUARY 2015 • VOL 347 ISSUE 6217 sciencemag.org SCIENCE
logical techniques, he distinguished persisters from resistant mutants, showed that
their levels could be enhanced by stress,
and anticipated that they would be in a
“dormant nondividing phase” and present
among other bacterial pathogens (2). The
recent exciting progress on mechanisms
of TA function establishes these toxins as
key inducers of the persister state. Future
research should elucidate the many functions of TAs and how they work collectively
during persistent bacterial infections. For
example, it is unclear whether different
stresses activate different TA subsets, and
what the profiles of toxin activation are in
individual bacterial cells. Some toxins have
been shown to be sequence-specific ribonucleases, but whether this specificity has
physiological implications is uncertain. It
could be that bacteria perceive signals that
trigger their exit from quiescence, but the
mechanisms involved are unknown.
If persisters lead to recurrent infections
requiring multiple courses of antibiotics, then they are likely to contribute appreciably to the current worldwide crisis
of antibiotic resistance. Yet, surprisingly
little is known about the relative usage of
antibiotics for persistent infections and
the degree to which persisters influence
the emergence of resistance. In the long
term, TAs and associated signaling molecules may provide targets for drugs that
can either prevent persisters from being
formed, or—perhaps more feasibly—coax
them out of the nonreplicating state so
that they resume susceptibility to antibiotics. This might finally enable complete
eradication of an otherwise recurrent or
persistent infection, so that, as Bigger put
it, “the success of penicillin therapy will
become more commensurate with its po-tentialities” (2). ■
REFERENCES AND NOTES
1. G. L. Hobby, K. Meyer, E. Chaffee, Exp.Biol.Med. 50, 281
2. J. W.Bigger, Lancet 244,497(1944).
3. J. L. Spudich, D. E. Koshland Jr., Nature 262, 467 (1976).
4. J.Casadesús,D.A.Low, J. Biol. Chem. 288,13929(2013).
5. N. Q. Balaban, J. Merrin, R. Chait, L. Kowalik, S. Leibler,
Science 305, 1622 (2004).
6. H. S. Moyed, K. P. Bertrand, J. Bacteriol. 155, 768 (1983).
7. E. Maisonneuve, L. J. Shakespeare, M. G. Jørgensen, K.
Gerdes, Proc. Natl. Acad. Sci. U.S.A. 108, 13206 (2011).
8. E. Maisonneuve, K. Gerdes, Cell 157, 539 (2014).
9. E. Rotem et al ., Proc. Natl. Acad. Sci. U.S. A. 107, 12541
10. E. Maisonneuve, M. Castro-Camargo, K. Gerdes, Cell 154,
11. A. Garcia-Pino et al., Cell 142, 101 (2010).
12. C. K. Okoro et al ., Clin. Infect. Dis. 54, 955 (2012).
13. B. Claudi et al ., Cell 158, 722 (2014).
14. S. Helaine et al ., Science 343, 204 (2014).
I thank S. Helaine and T. Thurston for helpful comments.
Lysosomes were discovered more than 60 years ago as highly acidic cellular organelles containing many enzymes responsible for breaking down mac- romolecules (1). Since then, their roles have expanded. Lysosomes function
in autophagy, the process that breaks down
cellular components to allow cell survival
and homeostasis in the face of starvation
(1). These organelles also have emerged as
a signaling hub for the enzyme mechanistic target of rapamycin (mTOR), a protein
kinase involved in cellular and organismal
growth responses to nutrient availability
(2). We also now recognize links between
aberrant lysosomal function and several diseases, including lysosomal storage diseases
(e.g., Tay-Sachs disease) and neurodegenerative disorders (e.g., Parkinson’s disease),
and also with aging (1). On page 83 of this
issue, Folick et al. ( 3) indicate how lysosomes
play a role in the latter—by deploying a lipid
molecule to the nucleus, whose impact on
gene expression extends life span in an animal model (the nematode Caenorhabditis
elegans). The study not only uncovers a lysosome-to-nucleus signaling pathway but also
highlights the potential of lipids in mediating long-range physiological effects.
Lysosomes contain about 60 enzymes,
including many well-conserved lipases involved in fatty acid breakdown. Defects in lysosomal acid lipase A (LIPA) lead to several
human lysosomal storage diseases, including
Wolman disease, a disorder characterized by
metabolic defects and death in childhood
( 4). In C. elegans, the LIPA homolog LIPL- 4
is highly expressed in specific conditions
that are linked to life-span extension ( 5, 6).
However, the mechanism by which this enzyme modulates aging has remained elusive.
Using a combination of genetics, metabo-
lomics, biochemistry, and immunocytochem-
istry, Folick et al. explored the molecular
mechanisms by which lysosomal LIPL- 4 ac-
tivation regulates aging in C. elegans. They
show that worms overexpressing LIPL- 4 live
substantially longer than normal worms and
produce increased amounts of several bioac-
tive lipids, notably the fatty acid oleoyletha-
nolamide (OEA). OEA is likely generated by
the breakdown of more complex lipids in the
lysosome by LIPL- 4. LIPL- 4–overexpressing
worms also exhibit an increased amount
of a fatty acid binding protein called lipid-
binding protein- 8 [(LBP- 8); the human ho-
molog is fatty acid binding protein (FABP)].
Elegantly coupling fluorescence imaging
with mutations that alter protein targeting
to the lysosome, Folick et al. demonstrate
that LIPL- 4 must reside within the lysosome
to extend life span. By contrast, LBP- 8 trans-
locates from the lysosome into the nucleus
to ensure increased longevity. As LBP- 8 can
directly bind to OEA, these results suggest
that LBP- 8 is a lipid chaperone assisting
OEA entry into the nucleus (see the figure).
What happens once OEA is shuttled into
the nucleus? Folick et al. found that OEA
physically binds to and activates conserved
nuclear hormone receptors, thereby activating the transcription of target genes. Fatty
acid ligands have been reported to control
the transcriptional activity of subfamilies
of nuclear receptors ( 7), and OEA can bind
to the nuclear receptor peroxisome proliferator–activated receptor-α (PPARα) in mice
( 8). The authors report that two particular
nuclear receptors—nuclear hormone recep-tor- 49 (NHR- 49) and NHR- 80, the C. elegans homologs of mammalian PPARα and
hepatic nuclear factor 4, respectively—are
both required for LIPL- 4–induced longevity,
and that OEA can directly bind to NHR- 80.
This observation is consistent with previous
reports that NHR- 49 and NHR- 80 play critical roles in life-span regulation in C. elegans
( 9, 10).
What about dietary supplementation of
OEA? Folick et al. found that feeding worms
OEA during their adult life is sufficient to
Lysosomal lipid lengthens
By Shuo Han and Anne Brunet
A fatty acid moves from the lysosome to the nucleus, altering
gene expression and extending longevity in the worm
Department of Genetics, Stanford University, Stanford, CA
94035, USA. E-mail: firstname.lastname@example.org
of fatty acids…has the
potential to delay aging.”