Interview Date: November 2009
From the Special Topic of
According to our Special Topics analysis on
autophagy, Dr. Patrice Codogno's work ranks at #9 by total
papers and at #10 by total cites, based on 39 papers cited
a total of 1,994 times. In
Essential Science IndicatorsSM from
Reuters, Dr. Codogno's record includes 56 papers, the
majority of which are classified under Biology &
Biochemistry, cited a total of 2,500 times between January
1, 1999 and June 30, 2009.
Dr. Codogno is a member of INSERM, and works out of the
Faculté de Pharmacie of the Université
Paris-Sud 11. In the interview below, he talks with
ScienceWatch.com about his research in autophagy.
Would you tell us a bit about your
educational background and research experiences?
I received my Ph.D. in 1984 from the University Pierre et Marie Curie in
Paris, France. Soon after being granted tenure at INSERM (National
Institute of Health and Medical Research) in 1985, I started studying the
role of glycosylation in the intracellular trafficking of proteins.
At the time, little was known about the role of N-glycans in the quality
control of proteins and membrane targeting, with the exception of that of
mannose 6-phosphate in lysosomal targeting. My current work is centered on
the biosynthesis of glycoproteins and extracellular matrix assembly.
What first interested you in autophagy, and is
there a specific aspect of autophagy research on which you
While studying the intracellular trafficking of N-linked glycoproteins in
human colon cancer cells, my team’s studies revealed slight trimming
of high-mannose glycans in the complex glycans in undifferentiated cells,
but not in differentiated cells. Lysosomal inhibitors and 3-methyladenine,
an inhibitor of autophagy, stabilized high-mannose glycoproteins in
undifferentiated cells without increasing the appearance of complex-type
These results were reported in a Journal of Biological Chemistry
paper in 1991 (Trugnan G, et al., "The N-glycan processing in
HT-29 cells is a function of their state of enterocytic
differentiation—evidence for an atypical traffic associated with
change in polypeptide stability in undifferentiated HT-29 cells,"
266:20849-55, 5 November 1991), and demonstrated that high-mannose
glycoproteins synthesized in the endoplasmic reticulum were diverted to the
lysosomal compartment instead of being transported to the Golgi apparatus.
These findings were the starting point for our subsequent studies of
"These studies show that a
pro-apoptotic molecule (ceramide) and an
anti-apoptotic molecule (Bcl-2) are also able
to regulate autophagy, implying that
cross-talk occurs between autophagy and
We soon decided to focus our research on the regulation of autophagy in
cancer cells, because at that time there was still little investigation of
the molecular aspect of autophagy and its relationship to tumorigenesis,
and not many groups were working in the field (things sure have changed
since then!). However, I should point out that I learnt a lot by reading
papers by Per O. Seglen, Alfred J. Meijer, E. Knecht, and Glenn Mortimore,
who were pioneers in the field.
Your most-cited paper in our analysis is the 2000
Journal of Biological Chemistry article, "Distinct classes of
phosphatidylinositol 3'-kinases are involved in signaling pathways
that control macroautophagy in HT-29 cells," (Petiot A, et
al., 275: 992-8, 14 January 2000). Would you talk a little bit
about this paper, its findings, and why it is so highly
The germ of this paper was sown when I met Alfred J. Meijer in 1996
at a proteolysis congress in Turku (Finland), where P.O. Seglen had
organized the first autophagy symposium...at a conference on proteolysis!
3-methyladenine (3-MA) was routinely used to inhibit the formation of
autophagosomes, based on the seminal paper from Seglen's laboratory in
1982. At the meeting, Fred Meijer reported that 3-MA inhibits autophagy by
interfering with the activity of phosphatidylinositol 3-kinases. His
findings were published a year later in FEBS Journal (the former
European Journal of Biochemistry).
My own team's contribution was to show that the inhibition of autophagy by
3-MA was due to the inhibition of class III PI3K or human Vps34, whereas
the inhibition of class I PI3K (which is upstream of mTOR) has a
stimulatory effect on autophagy. The role of Vps34 when complexed with the
autophagy protein Beclin 1 is an essential step in the formation of the
autophagosome, and is highly conserved among eukaryotic cells. Moreover, in
mammalian cells, the class-I PI3K signaling pathway plays a major role in
The modulation of autophagy is now recognized as being an important result
of the deregulation of PI3K observed in human diseases, such as cancer. The
initial report of the involvement of class-I and class-III PI3K in the
regulation of autophagy was therefore an important milestone in the field.
Last, but not least, this study marked the beginning of an extremely
stimulating and amicable collaboration with Fred Meijer.
Earlier this year, your group published another
paper in that same journal, "Role of JNK1-dependent Bcl-2
phosphorylation in ceramide-induced macroautophagy," (Pattingre S,
et al., Journal of Biological Chemistry 284: 2719-28, 30
January 2009). Could you tell our readers something about this
This work follows on from our initial report published in 2004 in the
Journal of Biological Chemistry on the role of ceramide as an
autophagy stimulator (Scarlatti F, et al., "Ceramide-mediated
macroautophagy involves inhibition of protein kinase B and up-regulation of
beclin 1," 279: 18384-91, 30 April 2004).
In our most recent study, we demonstrate that ceramide activates the
class-III PI3K complex and so stimulates autophagy. This stimulation is due
to a ceramide-dependent phosphorylation of Bcl-2 by JNK1. The
phosphorylation of Bcl-2 abolishes its inhibitory effect on autophagy by
abolishing its interaction with Beclin 1 in the class-III PI3K complex.
This mechanism is identical to that observed during the induction of
autophagy by starvation reported
Levine and her team (Wei et al. 2008 Mol.
Interestingly, Edinger and co-workers have reported that ceramide induces
starvation in cells by blocking amino acid transport. It therefore makes
sense to suggest that ceramide and amino acids use overlapping regulation
systems to control autophagy. These studies show that a pro-apoptotic
molecule (ceramide) and an anti-apoptotic molecule (Bcl-2) are also able to
regulate autophagy, implying that cross-talk occurs between autophagy
How has our knowledge of autophagy changed over the
"The modulation of autophagy is now
recognized as being an important result of
the deregulation of PI3K observed in human
diseases, such as cancer."
Enormously! It may be interesting here to compare autophagy and apoptosis.
A major breakthrough in apoptosis was the discovery of apoptosis genes in
C. elegans in the mid-1980s (although the term had first been
introduced in the early 1970s). The breakthrough in autophagy was the
discovery of ATG genes in yeast, which were first reported by Ohsumi and
co-workers in 1993 (the term autophagy had been coined in the early 1960s).
Subsequently, it was demonstrated that ATG5 and Atg6 (beclin 1) were
conserved in mammalian cells. Now we know that most of the Atgs involved in
the formation of autophagosomes are conserved in mammalian cells. The
development of mouse models has revealed the importance of stress-induced
autophagy and basal autophagy in tissue homeostasis and survival. Moreover,
having identified the role of autophagy in several human diseases is likely
to give rise to new approaches to treating neurodegenerative disease and
Two fascinating aspects of autophagy are the discovery of its function in
innate and acquired immunity, and, of course, its function as an
anti-ageing mechanism. Another interesting point is the fact that autophagy
is considered to be a non-selective mechanism—I am speaking here of
macroautophagy, although it is now clear that in many situations autophagy
is selective towards cell structures, proteins, and lipids. One may wonder
whether unselective autophagy should in fact be regarded as an exception
rather than the rule.
One major challenge that remains is to determine the origin of the
isolation membrane or "phagophore" (a term coined by P. Seglen 20 years
ago) that forms the autophagosomes. Undoubtedly, we can expect huge
progress to be made in this "Quest for autophagy" issue in the near future.
Where would you like to take your research on
autophagy in the next decade?
I am now interested in non-canonical forms of autophagy, by which I mean
forms of autophagy that do not use the whole set of Atg proteins to form an
autophagosome (18 in fact). Once again the story overlaps with that of
apoptosis, where morphology can involve several different molecular
elements. The discovery of non-canonical forms of autophagy points to
plasticity in the way autophagosomes are formed, and also in differences in
cell functions. Moreover, these forms of autophagy highlight the importance
of using an unrestricted panel of methods to measure autophagy. This may
also lead to a refining of the definition of macroautophagy.
Another interesting emerging field is that of the role of Atg proteins
independently of autophagy. Investigating these issues could be a way to
escape to the fringes of mainstream research, and away from areas that have
now become rather "crowded" and very competitive.
What would you say the "take-home message" about
your work should be?
I came into the field of autophagy by serendipity, at a time when autophagy
was not very fashionable in cell biology. It is fascinating for a scientist
to be involved in the development of a new field of research (even if one
only contributes a small brick to the wall), and even if it is sometimes
viewed as a research backwater by many people. We can hope that times have
changed, and autophagy is now an interesting challenge with possible
applications in many human diseases. So, my take-home message is, "Go for
it—just do it!"
Dr. Patrice Codogno
Faculté de Pharmacie
Université Paris-Sud 11
Petiot A, et al., "Distinct classes of
phosphatidylinositol 3'-kinases are involved in signaling
pathways that control macroautophagy in HT-29 cells,"
J. Biol. Chem. 275(2): 992-8, 14 January 2000.
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