Cell News 01/2017
16
AWARD WINNERS
Regulation of host-pathogen
interactions by the ubiquitin system
Evgenij Fiškin
1
& Ivan Dikic
1,2
1
Institute of Biochemistry II, Goethe University School of Med-
icine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
2
Buchmann Institute for Molecular Life Sciences, Goethe
University, Max-von-Laue-Str. 15, 60438 Frankfurt am Main,
Germany
Post-translational modification of proteins with ubiquitin (Ub)
serves as a critical signal in the host innate immune response
to diverse pathogenic stimuli. As such, ubiquitination drives
multiple layers of immune defense including the progression
of pattern recognition receptor signaling and the removal of
intracellular pathogens by selective autophagy. As a counter-
measure many pathogens have therefore evolved strategies to
exploit the host Ub system to promote their own survival. In
this regard, a large number of bacteria (e.g.
Salmonella
,
Shigel-
la, Legionella
or
E. coli
) inject their hosts with multiple viru-
lence effectors harboring Ub ligase or deubiquitinase activities.
By using multiple proteomic approaches we have monitored
dynamic changes in the global ubiquitinome of host epithelial
cells and invading pathogen during the course of a
Salmonella
Typhimurium infection. Our dataset reveals that
Salmonella
entry promotes host-driven formation of non-degradative
linear Ub-chains, which stimulate the activation of NF-
κ
B
and the production of pro-inflammatory cytokines. Analysis of
the linear ubiquitinome in infected cells uncovered previously
unknown targets of this Ub chain type and indicates the simul-
taneous activation of multiple inflammatory pathways upon
Salmonella
infection. Focusing on the function of bacterial Ub
ligase virulence effectors, we identify two host immune regula-
tory proteins TRIM56 and TRIM65 as novel substrates of the
orphan
Salmonella
HECT ligase SopA. Our structural, proteomic
and biochemical evidence suggests that SopA inhibits and
induces the proteasomal degradation of TRIM56 and TRIM65.
Mechanistically, SopA dampens TRIM56 and TRIM65-mediated
production of type I interferons to promote
Salmonella
patho-
genesis. Taken together, our findings point towards an unrec-
ognized role of the interferon response in
Salmonella
-induced
gastroenteritis.
Molecular control of the mammalian
oocyte-to-zygote transition
Kikue Tachibana-Konwalski
Institute of Molecular Biotechnology of the Austrian Academy
of Sciences (IMBA), Vienna, Austria
The most dramatic cell fate conversion occurs when high-
ly differentiated gametes – egg and sperm – fuse to form a
totipotent embryo with the potential to give rise to a new
organism. Female germ cells or oocytes are converted through
specialized cell division cycles, fertilization and epigenetic
reprogramming into the single-cell embryo or zygote. How
chromatin is reorganized and reprogrammed after fertilization
remain crucial questions in biology. Using a combination of
mouse genetics, epigenetics and 4D live-cell imaging, we have
discovered that zygotic reprogramming of sperm chromatin
proceeds via DNA lesions that require repair and this process
is monitored by a surveillance mechanism. To gain insights
into the 3D organization of chromatin during reprogramming
to totipotency, we developed a single-nucleus Hi-C protocol
that provides genome-wide spatial proximity information at
unprecedented resolution. Using genomics, mathematical mod-
elling and microscopy, we found that chromatin architecture is
uniquely reorganized during the mammalian oocyte-to-zygote
transition and is distinct for zygotic maternal and paternal
chromatin. We identified zygotic maternal chromatin as the
first interphase genome organized into loops and topologically
associating domains but lacking strong compartments. These
results demonstrate that the global chromatin organization
of zygotic genomes is fundamentally different from other
interphase cells. An understanding of the zygotic chromatin
“ground state” has the potential to provide insights into repro-
gramming to totipotency.
