Klebsiella pneumoniae Reduces SUMOylation To Limit Host Defense Responses

Abstract

Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Understanding the virulence mechanisms of K. pneumoniae is a priority and timely to design new therapeutics. Here, we demonstrate that K. pneumoniae limits the SUMOylation of host proteins in epithelial cells and macrophages (mouse and human) to subvert cell innate immunity. Mechanistically, in lung epithelial cells, Klebsiella increases the levels of the deSUMOylase SENP2 in the cytosol by affecting its K48 ubiquitylation and its subsequent degradation by the ubiquitin proteasome. This is dependent on Klebsiella preventing the NEDDylation of the Cullin-1 subunit of the ubiquitin ligase complex E3-SCF-βTrCP by exploiting the CSN5 deNEDDylase. Klebsiella induces the expression of CSN5 in an epidermal growth factor receptor (EGFR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-extracellular signal-regulated kinase (ERK)-glycogen synthase kinase 3 beta (GSK3β) signaling pathway-dependent manner. In macrophages, Toll-like receptor 4 (TLR4)-TRAM-TRIF-induced type I interferon (IFN) via IFN receptor 1 (IFNAR1)-controlled signaling mediates Klebsiella-triggered decrease in the levels of SUMOylation via let-7 microRNAs (miRNAs). Our results revealed the crucial role played by Klebsiella polysaccharides, the capsule, and the lipopolysaccharide (LPS) O-polysaccharide, to decrease the levels of SUMO-conjugated proteins in epithelial cells and macrophages. A Klebsiella-induced decrease in SUMOylation promotes infection by limiting the activation of inflammatory responses and increasing intracellular survival in macrophages. IMPORTANCE Klebsiella pneumoniae has been singled out as an urgent threat to human health due to the increasing isolation of strains resistant to “last-line” antimicrobials, narrowing the treatment options against Klebsiella infections. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of multidrug-resistant Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial research and development pipeline. Furthermore, there is still limited evidence on K. pneumoniae pathogenesis at the molecular and cellular levels in the context of the interactions between bacterial pathogens and their hosts. In this research, we have uncovered a sophisticated strategy employed by Klebsiella to subvert the activation of immune defenses by controlling the modification of proteins. Our research may open opportunities to develop new therapeutics based on counteracting this Klebsiella-controlled immune evasion strategy.

Staphylococcus aureus Decreases SUMOylation Host Response to Promote Intramacrophage Survival

“…While viruses have been reported to modulate SUMOylation [ 26 , 27 ], there are only a few reports describing the role of SUMOylation in bacterial intracellular survival. The impact of bacterial infection on this post-translational modification remains poorly studied [ 12 , 15 ]. The mechanisms by which pathogenic bacteria modulate host protein SUMOylation have only been recently investigated and remain poorly understood.…”

“…More recently, the adherent-invasive E. coli (AIEC) bacteria were shown to be able to inhibit autophagy by modifying host SUMOylation allowing intracellular replication [ 12 ]. Klebsiella pneumoniae is able to decrease SUMOylation to promote infection by limiting the activation of host inflammatory responses [ 15 ]. S. aureus is able to survive intracellularly by hijacking host cell defenses [ 6 ], but the putative role of host SUMOylation after S. aureus infection was unknown.…”

“…PTMs include phosphorylation, acetylation, methylation, and also the addition of small polypeptides such as ubiquitin or ubiquitin-like proteins such as the Small Ubiquitin-like Modifier (SUMO). Whereas several pathogens are known to use PTMs for their own benefit [ 7 , 8 , 9 , 10 , 11 ], only few pathogenic bacteria have been reported to interfere with the SUMOylation processes [ 12 , 13 , 14 , 15 , 16 ]. SUMOylation is a reversible eukaryotic PTM in which SUMO is covalently linked to the lysine residues of target proteins.…”

Neddylation Alleviates Methicillin-Resistant Staphylococcus aureus Infection by Inducing Macrophage Reactive Oxygen Species Production

“…The COP9 signalosome possesses metalloisopeptidase activity, which efficiently deneddylates NEDD8 from the Cullins family (58,59). Recently, Klebsiella pneumoniae was found to prevent the neddylation of Cullin1 of the ubiquitin ligase E3-SCF-TrCP complex by inducing CSN5 expression (60). CSN5 is also an important regulator of parasite protein degradation and participates in the effect of zinc ditiocarb against Entamoeba histolytica (61).…”

Ehrlichia TRP effectors: moonlighting, mimicry and infection

“…K. pneumoniae increases deSUMOylase SENP2 levels in the cytosol through K48 ubiquitylation and degradation by the ubiquitin proteasome (Sá-Pessoa et al . 2020 ). The direct SUMOylation of host proteins by intracellular bacteria was recently determined in studies where S. Typhimurium mediated the host endocytic vesicular transport pathway (VTP) through SUMOylation of RAB7, a key component of VTP (Mohapatra et al .…”