Cell News 02/2017
10
of SopA (Fig. 3b). Using biochemical analysis, we elucidated the
substrate recognition mechanism of SopA, which recognizes
these two TRIM proteins by binding their catalytic RING domain.
Despite the presence of multiple hundred RING domain-containing
proteins in the human proteome, we find SopA to harbor incred-
ible specificity for its two targets TRIM56 and TRIM65. By solv-
ing the crystal structure of SopA in complex with the TRIM56
RING domain, we addressed the atomic basis of this selectivity
(Fig. 3c). Moreover, our biochemical and structural data indicate
that SopA-mediates inhibition of its two targets via a dual
mechanism. On the one hand SopA binding to the TRIM RING
domain dampens TRIM E3 ligase activity by obstructing the
RING-E2 binding site, while on the other hand SopA´s HECT-like
activity mediates ubiquitination and proteasomal degradation
of TRIM56 and TRIM65. Previous work has demonstrated the
involvement of TRIM56 and TRIM65 in the stimulation of type
I interferon expression upon detection of foreign nucleic acids
(Kamanova et al., 2016). In light of these reports, our identifi-
cation of bacterial intervention via an inhibitory SopA-TRIM56/
TRIM65 relationship suggests an uncharacterized function of
interferons in gastroenteritis (Fig. 3d).
Conclusions and outlook
The presented results illustrate the broad impact that ubiquiti-
nation has during an infection with Gram negative bacterial
pathogens. In this context, Ub driven processes range from
the control of invasion and inflammation to the regulation
of cellular autophagy and endo-lysosomal systems. Our work
identifies a large number of previously unknown host-pathogen
interaction nodes providing a rich resource for future studies. In
particular, the identification of interferon-regulating TRIM E3
ligases as host targets of the
Salmonella
effector ligase SopA
suggests a so far unappreciated role for type I interferon in the
intestinal pathogenesis of S. Typhimurium and opens up multiple
new lines of investigation.
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