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bioRxiv · 10.64898/2026.03.06.710069

A bacterial effector blocks SUMOylation by steric occlusion of UBC9 via arginine-GlcNAcylation

Li, B.·Ma, Z.·Zhu, Y.·Zhao, Y.·Wang, X.·Zhang, H.
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Abstract

The post-translational modifier SUMO is crucial for host antimicrobial defense. Here, we discover that Salmonella employs a unique strategy to dismantle the host SUMOylation machinery. Salmonella infection robustly inhibits global SUMOylation, particularly SUMO2/3 conjugation, without altering the expression of SUMO-cycle enzymes. Genetic screening identified the T3SS-2 effector SseK1 as both necessary and sufficient for this suppression. SseK1, an arginine-GlcNAcyltransferase, directly binds and specifically modifies the SUMO E2-conjugating enzyme UBC9 at arginine 17 (R17). Structural and biophysical analyses revealed that GlcNAcylation at R17 sterically hinders UBC9s interaction with SUMO, thereby inactivating the entire SUMOylation cascade. A unique C-terminal lid domain (ARHVQ motif) in SseK1 confers substrate specificity for UBC9, representing an evolutionary innovation within Salmonella genus. Quantitative SUMOylome profiling demonstrated that SseK1-mediated UBC9 inactivation reprograms the host SUMOylation landscape, impairing the modification of key immune regulators such as MyD88, Hspa8 and destabilizing proteins like PDCD4. Consequently, this mechanism is critical for Salmonella intracellular survival and systemic virulence in mice. Our study unveils a unique bacterial strategy to dismantle the host SUMOylation machinery via precise enzymatic inactivation of its central hub.

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Li, B., Ma, Z., Zhu, Y., Zhao, Y., Wang, X., Zhang, H.. 2026-03-08. A bacterial effector blocks SUMOylation by steric occlusion of UBC9 via arginine-GlcNAcylation. https://doi.org/10.64898/2026.03.06.710069

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