Abstract
Disruption of the sumoylation/desumoylation equilibrium is associated with several disease states such as cancer and infections, however the mechanisms regulating the global SUMO balance remain poorly defined. Here, we show that infection by Shigella flexneri, the causative agent of human bacillary dysentery, switches off host sumoylation during epithelial cell infection in vitro and in vivo and that this effect is mainly mediated by a calcium/calpain-induced cleavage of the SUMO E1 enzyme SAE2, thus leading to sumoylation inhibition. Furthermore, we describe a mechanism by which Shigella promotes its own invasion by altering the sumoylation state of RhoGDIα, a master negative regulator of RhoGTPase activity and actin polymerization. Together, our data suggest that SUMO modification is essential to restrain pathogenic bacterial entry by limiting cytoskeletal rearrangement induced by bacterial effectors. Moreover, these findings identify calcium-activated calpains as powerful modulators of cellular sumoylation levels with potentially broad implications in several physiological and pathological situations.
Highlights
The post-translational modification by SUMO is an essential regulatory mechanism of protein function that is involved in most challenges faced by eukaryotic cells, ranging from cell communication to gene expression (Cubenas-Potts and Matunis, 2013; Flotho and Melchior, 2013)
Shigella infection inhibits sumoylation in epithelial cells in vitro and in the gut To investigate the impact of Shigella infection on global sumoylation of host cell proteins, we followed the global pattern of proteins conjugated to SUMO1 and SUMO2/3 at timed intervals after infection (0 to 180 min)
We evaluated the functional consequences of loss of sumoylation on the pathogenicity of Shigella in human epithelial cells depleted for UBC9 using siRNAs and tamoxifen-inducible Ubc9 KO mouse embryonic fibroblasts (MEFs) (Demarque et al, 2011)
Summary
The post-translational modification by SUMO is an essential regulatory mechanism of protein function that is involved in most challenges faced by eukaryotic cells, ranging from cell communication to gene expression (Cubenas-Potts and Matunis, 2013; Flotho and Melchior, 2013). The steady-state levels of sumoylated substrates are critically regulated by the action of desumoylating enzymes, such as SENPs. Sumoylation is characterized by its highly dynamic and reversible nature, resulting in only a very small fraction of a given protein substrate being sumoylated in the cell at steady state level (Nayak and Muller, 2014). While information on the specific roles of the different SUMO E3 and SENP enzymes is accumulating, our knowledge of possible mechanisms regulating the global sumoylation/desumoylation equilibrium still remains highly fragmentary
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
