26 Jun The transcription factor TFEB has been proposed to be the master regulator of autophagy
Question
Autophagy’s Top Chef
Ana Maria Cuervo
Science 332, 1392 (2011);
DOI: 10.1126/science.1208607
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PERSPECTIVES
CELL BIOLOGY
Autophagy’s Top Chef
The transcription factor EB both controls
lysosome formation and increases autophagy
in cells experiencing starvation.
Ana Maria Cuervo
Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center and Institute for Aging
Studies, Albert Einstein College of Medicine, Bronx, NY
10461, USA. E-mail: ana-maria.c[email protected].yu.edu
1392
tion by extracellular signal–regulated kinase
2 (ERK2), a member of the mitogen-activated protein (MAP) kinase family. During
starvation, however, reduced phosphorylation by ERK2 leads to mobilization of TFEB
into the cell nucleus, and to the activation of
a dual transcriptional program that generates
new lysosomes and increases autophagy.
Most cells have relatively high amounts
of Atgs under normal circumstances. As a
result, during the first hours of starvation, a
cell should be able to make autophagosomes
with whatever Atgs are already in the cytosol.
If starvation persists, however, then depletion of Atgs could limit the ability of a cell to
generate new autophagosomes. Researchers
once believed that, in many cells, this type of
Downloaded from www.sciencemag.org on August 18, 2011
is starving, it makes sense that autophagy
m ay not need transcriptional activation.
Why “spend” resources and energy synthesizing new Atgs when the whole purpose of
activating autophagy during starvation is to
salvage and recycle amino acids to sustain
protein synthesis?
Settembre et al. show that, even under
starvation conditions, cells produce new
Atgs. Two years ago, this same research
g roup identified a gene network that controls the formation of the lysosome (10).
Now, they show that the master regulator
of that program, TFEB, is also in charge of
the autophagic transcriptional program during cell starvation. They found that TFEB is
retained in the cytosol through phosphoryla-
NUCLEUS
TFEB
CYTOPLASM
ERK2
Lysome
Autophagosome
Ribosome
Lysomal proteins
Autophagosome proteins
mRNA
Mitochondria
Protein
Controlling autophagy. Phosphorylation of TFEB (upper left) by ERK2 retains it in the cytosolic compartment. Upon starvation, reduced ERK2-dependent phosphorylation of TFEB mobilizes it to the nucleus, where
it activates a transcription program that controls the formation of both lysosomes (lower left) and genes
involved in different steps in the autophagic process (lower right). The TFEB-mediated increase in number
of lysosomes and autophagosomes and their faster fusion enhances autophagic degradation.
17 JUNE 2011 VOL 332 SCIENCE www.sciencemag.org
Published by AAAS
CREDIT: P. HUEY/SCIENCE
I
n cells, organelles called lysosomes are
responsible for breaking down a wide
range of cellular material, such as proteins and other organelles, through a process known as autophagy (1). When nutrients are scarce, autophagy allows a cell to
break down its own components and recycle important molecules (2). Autophagy
involves about 35 autophagy-related genes
(ATGs); these genes generate multiprotein
complexes that act sequentially (3), much as
kitchen assistants work in sequence to prepare a meal. Most of these autophagy assistants have been identified, but not a master
chef. On page 1429 of this issue, Settembre
et al. (4) describe how transcription factor
EB (TFEB), which is already known to coordinate lysosome formation, functions as the
master chef of autophagy when cells are
starving.
Cells can move cytosolic materials (the
cargo) to the lysosomal compartment in
many ways. One that has received more
attention in recent years involves the use
of double-membrane vesicles (autophagosomes) as carriers. Autophagosomes form
when whole cytosolic regions or specific
organelles are sequestered by a membrane
(phagophore) that wraps around them, and
then sequesters and seals the selected cargo
from the rest of the cytosol (2). Degradation
inside autophagosomes occurs when lysosomes fuse with the autophagosome and
infuse it with enzymes that break down the
cargo (see the figure).
In recent years, investigators have
exquisitely dissected the many autophagyrelated proteins (Atgs) that participate in
this process. This work has revealed that
the sequestering membrane is constructed
from lipids and proteins shuttled from different organelle membranes (5). We have
a good idea about how the cargo is recognized (6), what moves the autophagosomes
around the cell (7), and how they fuse with
lysosomes ( 8 , 9 ). However, researchers
have questioned the existence of, or even
the need for, a master orchestrator of ATG
transcription. Autophagy can occur independently of transcription, and when a cell
PERSPECTIVES
Other transcriptional regulators increase
the expression of Atgs, but often only those
Atgs involved in the early steps of autophagosome formation (13, 14). The strength of
the TFEB-mediated program is that it affects
the whole process; it not only generates
more autophagosomes, but also accelerates
their delivery to lysosomes and, by increasing the number of available lysosomes,
f acilitates the rapid degradation of substrates. This aspect of the autophagy process
is often overlooked. Forming autophagosomes and secluding the materials from the
cytosol is not enough. The ultimate purpose
of autophagy is to break down the cargo and
recycle essential macromolecules, and this
only occurs once the lysosomal hydrolases
reach the autophagosome through fusion.
Defective autophagy has been linked to
common human diseases such as neurodegenerative conditions (e.g., Alzheimer’s
disease, Parkinson’s disease), metabolic disorders (diabetes, obesity), and aging. The
formation of autophagosomes is intact or
even enhanced in many of these pathologies;
it is the failure to degrade these structures
that compromises cellular viability (15).
Pharmacological interventions have succeeded in enhancing autophagosome formation by suppressing negative regulators. The
main concern about this approach, however,
is that it could lead to an “autophagic traffic
jam” if the cell does not have enough lysosomes to receive all the cargo. The ability of
TFEB to control the formation of both lysosomes and autophagosomes makes it a very
attractive target for developing new therapies for those conditions in which enhanced
autophagy is desirable.
References and Notes
1. Z. Yang, D. J. Klionsky, Nat. Cell Biol. 12, 814 (2010).
2. N. Mizushima, A. Yamamoto, M. Matsui, T. Yoshimori,
Y. Ohsumi, Mol. Biol. Cell 15, 1101 (2004).
3. Z. Yang, D. J. Klionsky, Curr. Opin. Cell Biol. 22, 124
(2010).
4. C. Settembre et al., Science 332, 1429 (2011); 10.1126/
science.1204592
5. K. Suzuki, Y. Ohsumi, FEBS Lett. 584, 1280 (2010).
6. T. Lamark, V. Kirkin, I. Dikic, T. Johansen, Cell Cycle 8,
1986 (2009).
7. J. L. Webb, B. Ravikumar, D. C. Rubinsztein, Int. J. Biochem. Cell Biol. 36, 2541 (2004).
8. J.-Y. Lee et al., EMBO J. 29, 969 (2010).
9. M. Razi, E. Y. Chan, S. A. Tooze, J. Cell Biol. 185, 305
(2009).
10. M. Sardiello et al., Science 325, 473 (2009).
11. R. Singh et al., Nature 458, 1131 (2009).
12. L. Yu et al., Nature 465, 942 (2010).
13. D. A. M. Salih, A. Brunet, Curr. Opin. Cell Biol. 20, 126
(2008).
14. P. Xu, M. Das, J. Reilly, R. J. Davis, Genes Dev. 25, 310
(2011).
15. E. Wong, A. M. Cuervo, Nat. Neurosci. 13, 805 (2010).
10.1126/science.1208607
PLANT SCIENCE
Plants Get Hyp to O-Glycosylation
Debra Mohnen1 and Mary L. Tierney2
T
he two most abundant natural organic
polymers on Earth are cellulose and
chitin, characterized by long chains
of carbohydrates that bear a specific type of
sugar linkage called O-glycosylation. This
type of linkage also occurs between polysaccharides (glycans) and proteins and glycans
and lipids, yielding glycoconjugates that are
well known to function in cell recognition
processes (1). On page 1401 in this issue,
Velasquez et al. (2) explore a specific type of
O-glycosylation for plant cell wall structural
proteins and connect this modification to root
hair growth.
Two types of sugar linkages predominate
in glycoproteins: N-linkage of glycans to
asparagine residues, and O-linkages, which
Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, BioEnergy Science Center, University
of Georgia, Athens, GA 30602, USA. 2Department of Plant
Biology, University of Vermont, Burlington, VT 05405, USA.
E-mail: [email protected].uga.edu; mary.[email protected].edu
1
are structurally more complex and most
commonly connect glycans to the hydroxyl
group of serine or threonine residues. Glycans, however, can also be attached to lysine
or proline (Pro) if these amino acids are first
hydroxylated. This type of O-glycosylation is
addressed by Velasquez et al.
Hydroxyproline (Hyp) is prevalent in animal extracellular matrix structural proteins
such as collagen, and in hydroxyprolinerich glycoproteins (HRGPs) such as those
found in the plant cell wall. Hyp, however,
also occurs in regulatory proteins such as
Argonaute 2 in RNA silencing (3), the transcription factor HIF-1α (4), Cle peptides that
control plant cell differentiation (5), and hypsystemins that signal for plant defense (6).
The enzymes that catalyze Pro hydroxylation include prolyl 4-hydroxylases (P4Hs)
(7). The conversion of Pro to Hyp affects
protein conformation and protein-protein
interactions, and provides reactive hydroxyl
The polarized growth of plant root hair cells
requires specific glycosylation of proteins
in the plant cell wall.
groups for further modification such as glycosylation. The model plant Arabidopsis
thaliana encodes 13 P4Hs, but only P4H1
(8) and P4H2 (9) have been characterized at
the molecular level. Arabidopsis has at least
166 HRGP superfamily members, many
of which are differentially expressed during plant growth. The extent of HRGP prolyl hydroxylation can be predicted (10), and
establishes the HRGP glycosylation profile.
Velasquez et al. focused on HRGP function in Arabidopsis roots hairs (see the figure), tractable cells that elongate by polarized growth. Inhibition of P4H activity
blocked root hair growth and reduced the
O-glycosylation of an extracellular matrix
HRGP. The authors identified three P4Hs
that are highly expressed in root hair cells
(P4H2, 5, and 13), and observed that the
corresponding mutants exhibited reduced
root hair length, a decrease in total root Hyp
content and, for P4H2, reduced root hair
www.sciencemag.org SCIENCE VOL 332 17 JUNE 2011
Published by AAAS
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autophagy did not last more than 6 to 8 hours
into starvation. Recent studies, however, suggest that it can continue for days, with the
degradation process shifting from proteins to
more energetically favorable cargos, such as
intracellular lipids (11), over time.
How are cells sustaining autophagy over
these longer periods? Recycling of Atgs is
one possibility. Some of the structural components of the autophagosome, for example,
are recycled back to the cytosol before they
fuse with lysosomes (3, 5). This recycling
also applies to the lysosomal compartment
itself. During starvation, the vast increase in
autophagosome formation often means that
all existing lysosomes are engaged in fusing with newly formed autophagosomes.
As starvation persists, cells also actively
recycle components of the lysosomal membrane out of the hybrid vesicles (autophagolysosomes) ( 1 2 ) . B ut most lysosomal
enzymes—which are the ones that get the
degradative job done—are not retrieved out
of the autophagolysosomes. As a result, new
synthesis of lysosomal hydrolases may be
necessary to transform recycling vesicles
into functional lysosomes. The activation of
TFEB during starvation provides a solution
for both Atg consumption and the need for
new lysosomes.
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