Hidde Ploegh: immunologist, journeyman. Interview by Nicole LeBrasseur.
ABSTRACT From the moment he finished his Ph.D., Hidde Ploegh has been a wanted man. Invited to join one institution after another, he always packed with him his keen interests in the immune system.
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ABSTRACT: All members of the herpesviridae contain within their large tegument protein a cysteine protease module that displays deubiquitinating activity. We report the crystal structure of the cysteine protease domain of murine cytomegalovirus M48 (M48(USP)) in a complex with a ubiquitin (Ub)-based suicide substrate. M48(USP) adopts a papain-like fold, with the active-site cysteine forming a thioether linkage to the suicide substrate. The Ub core participates in an extensive hydrophobic interaction with an exposed beta hairpin loop of M48(USP). This Ub binding mode contributes to Ub specificity and is distinct from that observed in other deubiquitinating enzymes. Both the arrangement of active-site residues and the architecture of the interface with Ub lead us to classify this domain as the founding member of a previously unknown class of deubiquitinating enzymes.Molecular Cell 04/2007; 25(5):677-87. · 15.28 Impact Factor
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ABSTRACT: Human cytomegalovirus (HCMV) down-regulates expression of MHC class I products by selective proteolysis. A single HCMV gene, US11, which encodes an endoplasmic reticulum (ER) resident type-I transmembrane glycoprotein, is sufficient to cause this effect. In US11+cells, MHC class I molecules are core-glycosylated and therefore inserted into the ER. They are degraded with a half-time of less than 1 min. A full length breakdown intermediate that has lost the single N-linked glycan in an N-glycanase-catalyzed reaction transiently accumulates in cells exposed to the protease inhibitors LLnL, Cbz-LLL, and lactacystin, identifying the proteasome as a key protease. Subcellular fractionation experiments show this intermediate to be cytosolic. Thus, US11 dislocates newly synthesized class I molecules from the ER to the cytosol, where they are acted upon by an N-glycanase and the proteasome.Cell 04/1996; 84(5):769-79. · 31.96 Impact Factor
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ABSTRACT: Relatively small genomes and high replication rates allow viruses and bacteria to accumulate mutations. This continuously presents the host immune system with new challenges. On the other side of the trenches, an increasingly well-adjusted host immune response, shaped by coevolutionary history, makes a pathogen's life a rather complicated endeavor. It is, therefore, no surprise that pathogens either escape detection or modulate the host immune response, often by redirecting normal cellular pathways to their advantage. For the purpose of this chapter, we focus mainly on the manipulation of the class I and class II major histocompatibility complex (MHC) antigen presentation pathways and the ubiquitin (Ub)-proteasome system by both viral and bacterial pathogens. First, we describe the general features of antigen presentation pathways and the Ub-proteasome system and then address how they are manipulated by pathogens. We discuss the many human cytomegalovirus (HCMV)-encoded immunomodulatory genes that interfere with antigen presentation (immunoevasins) and focus on the HCMV immunoevasins US2 and US11, which induce the degradation of class I MHC heavy chains by the proteasome by catalyzing their export from the endoplasmic reticulum (ER)-membrane into the cytosol, a process termed ER dislocation. US2- and US11-mediated subversion of ER dislocation ensures proteasomal degradation of class I MHC molecules and presumably allows HCMV to avoid recognition by cytotoxic T cells, whilst providing insight into general aspects of ER-associated degradation (ERAD) which is used by eukaryotic cells to purge their ER of defective proteins. We discuss the similarities and differences between the distinct pathways co-opted by US2 and US11 for dislocation and degradation of human class I MHC molecules and also a putatively distinct pathway utilized by the murine herpes virus (MHV)-68 mK3 immunoevasin for ER dislocation of murine class I MHC. We speculate on the implications of the three pathogen-exploited dislocation pathways to cellular ER quality control. Moreover, we discuss the ubiquitin (Ub)-proteasome system and its position at the core of antigen presentation as proteolysis and intracellular trafficking rely heavily on Ub-dependent processes. We add a few examples of manipulation of the Ub-proteasome system by pathogens in the context of the immune system and such diverse aspects of the host-pathogen relationship as virus budding, bacterial chromosome integration, and programmed cell death, to name a few. Finally, we speculate on newly found pathogen-encoded deubiquitinating enzymes (DUBs) and their putative roles in modulation of host-pathogen interactions.Advances in Immunology 02/2006; 92:225-305. · 7.26 Impact Factor
People & Ideas
JCB • VOLUME 179 • NUMBER 3 • 2007 364
from all sides of the equation and on both
sides of the Atlantic. As a bicontinental
graduate student, Ploegh fi rst entered the
competitive world of immunology by
cloning a cDNA for a human major
histocompatibility complex (MHC) mole-
cule (1)—one of the glycoproteins that
present antigens on the cell surface.<ID>JCB1793pi1.eps</ID>
Since then, his focus on MHC has not
wavered, although it has broadened. In ad-
lternating between positions in
Europe and the U.S., Hidde
Ploegh has studied immunology
dition to MHC syn-
thesis and traffi ck-
ing (2), Ploegh has
also studied patho-
gens that hide by
(3) and the cellular
pathways that pro-
vide MHCs with
their antigens, in-
cluding the ubiqui-
system. He has developed new chemical
tools to study proteasome activity and
the roles of lysosomal and ubiquitin-
specifi c proteases (4).
In 2005, Ploegh joined the Whitehead
Institute, whose members hold faculty
appointments at MIT. He recently discussed
with us the career path that led him there,
what he sees as some of the drawbacks of
doing research at a medical school, and
his zest for fi shing and science.
What fi rst piqued your interest in
As an undergrad, I read an interview in
the Dutch equivalent of Ladies’ Home
Journal with one of the leading Dutch
immunologists, Jon van Rood. I wrote
him a letter asking whether I could work
in his lab, but I never got an answer.
At the time, I was working for my
undergraduate advisor, whose interests
were in bacterial cell walls and membrane
structure. He had some fi nancial resources
to allow his graduate students to go abroad
to learn techniques and bring these back
to his lab.
Since his two graduate students weren’t
particularly interested in this opportunity,
he turned to me. He wrote letters explain-
ing the purpose to a number of investiga-
tors, mostly in the U.S. One of the few
who wrote back in the affi rmative was
Jack Strominger, who was working at
Harvard on bacterial cell wall synthesis.
To my surprise—this was before Internet
days—when I arrived, it turned out that half
the Strominger lab was working on the bio-
chemistry of transplantation antigens. Then
and there, it became clear to me that that
would be a great topic to return to. My six-
month visit concluded with an agreement
that I’d return as a graduate student and
work on transplantation antigens.
For that, I got some fi nancial support
from the Dutch government. And who
should be sitting on the selection commit-
tee but van Rood. As luck would have it,
he even became my formal thesis advisor.
I did the practical work for my graduate
studies in Jack Strominger’s lab, but de-
fended my thesis in the Netherlands.
In 1980, I left the Strominger lab and
took my fi rst independent position.
You never did a postdoc?
Correct. My thesis project consisted of
cloning cDNA for a major histocompatibili-
ty antigen. I think that work attracted the
attention of Klaus Rajewsky, who was the
head of immunology at the University of
Cologne in Germany. He wondered wheth-
er I would be interested in taking a junior
group leader position at that institute.
What was it like, running a lab directly
after your Ph.D.?
I think the fi rst students you work with
suffer the consequences. You have no ex-
perience leading a lab, you make all the
mistakes that you can make. Objectively
speaking, not much was produced, but I
do think I learned how not to run a lab.
But you didn’t stay there long. In fact,
you rarely seem to stay at any one place
No, my next slot was at the Netherlands
Cancer Institute. I was invited to join in
1984 by Piet Borst. He had just become
the institute’s director and was interested
in infusing some fresh blood. I led a group
in the cell biology and biochemistry of
In ’92 I was approached by Susumu
Tonegawa. He asked whether I might be
interested in moving to MIT. That was an
opportunity that I couldn’t turn down.
I stayed there until ’97, when Harvard
Medical School wanted to know if I was
interested in moving there. I had gotten to
know several colleagues there when we
served as editors for Immunity. I also had
a very strong interest in the didactic mis-
sions of school, and they were looking for
a person to take charge of the graduate
program in immunology.
That lasted until 2005, and then I was
recruited to Whitehead.
How was returning to the States in the
I think the scientifi c climate in the U.S. to
this day is more vibrant and lively than
most places in Europe. I’m not dinging
Europe in the least, I enjoyed every moment
From the moment he fi nished his Ph.D., Hidde Ploegh has been a wanted man.
Invited to join one institution after another, he always packed with him his
keen interests in the immune system.
<doi>10.1083/jcb.1793pi</doi><au>Nicole LeBrasseur</au><cor>firstname.lastname@example.org</cor><dochead>People & Ideas</dochead><doctopic>News</doctopic><misc>Text and Interview by Nicole LeBrasseur</misc>Hidde Ploegh: Immunologist, journeyman
can produce so
PEOPLE & IDEAS • THE JOURNAL OF CELL BIOLOGY365
Text and Interview by Nicole LeBrasseur
I lived in Amsterdam, but I think the in-
tensity with which people pursue their
science is just on a different level. 15
years ago, that was certainly true, al-
though the difference seems to be less
pronounced today. The resources available,
the intellectual fi repower, the Boston
academic climate with MIT, Harvard,
and Harvard Medical School, it’s just
You seem to have an affi nity for the
Yes, I do. As it happens, I like to fi sh. I
would say Boston is the saltwater fl y-fi sh-
ing capital of the world. I co-own a little
fi shing boat, The Rampage, with my
Harvard colleague, Fred Alt. We go out
for striped bass, bluefi sh, bluefi n tuna
with varying degrees of success.
What made you decide to leave Harvard
Medical School for Whitehead/MIT?
<ID>JCB1793pi2.eps</ID>There are several issues associated with
working at a medical school. Many have
hospitals affi liated with them, and the eco-
nomics and logistics of that imposes a
certain organizational structure. The primary
mission of a medical school is naturally to
train doctors. To give you an example, I
had to talk to the head of our public affairs
department two years in a row before the
annual Dean’s report began highlighting
the various graduate programs. It would
showcase the medical students and the
M.D./Ph.D. students, but the graduate pro-
grams seemed like an afterthought.
I felt that the Whitehead/MIT environ-
ment was more curiosity driven and less
concerned with medically relevant re-
search. There’s nothing wrong with that
in principle, but for me, it’s like the differ-
ence between Italian and French cuisine.
They’re both outstanding if properly pre-
pared, but some people prefer French,
others, Italian. It has nothing to do with
quality per se, just a difference in style.
My recent research interests are also
better aligned with what MIT is really
good at: chemistry, materials science, engi-
neering, and so forth. Lately, I’ve become
more and more interested in engineering-
based approaches to biological questions.
If you enter the building where the
mechanical engineers are, and you see the
posters on the wall, you’ll see so much
ingenuity, such diversity of approaches.
I’m always struck by the eagerness of
faculty in other departments to get in-
volved, get their hands dirty, think about
possibilities for joint projects. There’s a
growing awareness that interdisciplinary
interactions—where one can combine,
say, physics with biology—can produce
so much more. Compare that with your
typical medical school, where everything
of necessity is focused on either basic
biology or translational stuff.
WHERE THE PASSION LIES
In all your locales, one constant has
been your interest in MHCs.
Yes, that is perhaps unusual. Most graduate
students change tack when they do a post-
doc and maybe again once they become
independent, but I haven’t really felt the
need. The work I started as a graduate
student still continues today, in a different
incarnation, of course. Ever since I start-
ed working on these MHC products, I’ve
been interested in how they’re put to-
gether from their building blocks, how
they travel from the site of synthesis to
Another unusual aspect of your career
is that you were always invited to your
True, I’ve never even applied for a job. I
have been in a very privileged position,
but I think a big part of it is just being
enthusiastic about what you do.
What I’ve learned is that the single
most important thing is passion. You also
have to take pleasure in the details: the
duplicates of a calibration curve falling
right on top of one another or bands on a
gel coming out razor sharp, in addition to
real discoveries. To this very day, there’s
almost nothing I’d rather do than look at
autorads. Get a life, right?
And why do you have such a passion
It’s the most exciting profession I could
imagine. It’s like a stem cell, continuous-
ly self-renewing. The next day is almost
always as exciting as the preceding one.
It’s hard to imagine fi nding a work-
ing environment that is so dependent on
the social aspects. Many students are
under the mistaken impression that be-
ing a scientist means being somewhat of
a recluse. Some future medical students
think that because they see patients, they
get a richer experience of interpersonal
interactions. Sure, if you enjoy dealing
with HMOs rather than working with
your peers, debating puzzles, and think-
ing creatively… But I know which side
my bread is buttered on.
1. Ploegh, H.L., et al. 1980. Proc. Natl. Acad.
2. Loureiro, J., and H.L. Ploegh. 2006.
Adv. Immunol. 92:225–305.
3. Wiertz, E.J., et al. 1996. Cell. 84:769–779.
4. Schlieker, C., et al. 2007. Mol. Cell.
<nohtml>“What I’ve learned is
that the single most
important thing is passion.
You also have to take
pleasure in the details.”
Ploegh and fi shing partners Tom Look (middle)
and Fred Alt (right) enjoy fishing for ideas
and the occasional bluefi n tuna.