Bacterial E3 Ubiquitin Ligase IpaH4.5 of Shigella flexneri Targets TBK1 To Dampen the Host Antibacterial Response

Abstract

IFN regulatory factors play a pivotal role in many cellular processes, including inflammatory and immune responses. Their activation is tightly regulated by TANK-binding kinase 1 (TBK1). In response to microbial components, TBK1 activates IFN regulatory factor 3 (IRF3) and cytokine expression. In this article, we show that TBK1 is a novel target of the IpaH4.5 protein, a Shigella type III effector possessing E3 ubiquitin ligase activity. Remarkably, IpaH4.5 interacts with TBK1 and promotes its K48-linked polyubiquitylation. Consequently, polyubiquitylated TBK1 undergoes proteasome-dependent degradation, which perturbs the phosphorylation, nuclear translocation, and activation of IRF3. Because IRF3 and TBK1 are required for restricting Shigella growth, we propose that the polyubiquitylation and degradation of TBK1 during Shigella infection are new bacterial strategies to modulate the host antibacterial responses.

Shigellaeffector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation

“…These observations imply that each IpaH family protein has a diverse array of host target proteins due to its unique subcellular localisation and substrate recognition domain and thus makes a distinct contribution to promotion of bacterial pathogenesis. Consistent with this, recent studies have revealed the roles of IpaH family members in disabling target proteins in host cells (de Jong et al, ; Li et al, ; Wandel et al, ; Zheng et al, ).…”

“…Shigella possesses 12 ipaH genes, which encode IpaH proteins that injected into host cells via the T3SS (Otsubo, Kim, Lee, & Sasakawa, ; Rohde, Breitkreutz, Chenal, Sansonetti, & Parsot, ; Singer et al, ; Zhu et al, ). IpaH family proteins contain N‐terminal leucine‐rich repeats (LRRs) and have E3 ubiquitin ligase activity in their conserved C‐terminal regions (CTRs; de Jong, Liu, Chen, & Alto, ; Li et al, ; Wandel et al, ; Zheng et al, ). IpaH family proteins are widely conserved among animal and plant pathogens, including Shigella (IpaH), Salmonella (SspH1, SspH2, and SirP), Edwardsiella , Bradyrhizobium , Rhizobium , and some Pseudomonas species, implying that these effectors play important roles in bacterial infection (Quezada, Hicks, Galan, & Stebbins, ).…”

“…For example, p65 of the nuclear factor kappa‐light‐chin‐enhancer of activated B cells (NFκB), which is involved in modulating the acute inflammatory response, undergoes ubiquitination by IpaH4.5 (Wang et al, ). In addition, TANK‐binding kinase 1 (TBK1) undergoes degradation via the ubiquitin–proteasome system (UPS), thereby interfering with type I interferon production and diminishing host antibacterial responses during Shigella infection (Zheng et al, ). However, little is known about the physiological role of IpaH4.5 in bacterial infection.…”

The Emerging Roles of STING in Bacterial Infections

“…Indeed, in ERGIC occurs most of STING-mediated signal transduction, correlating with TBK1 recruitment and downstream signaling [29]. During a regular infection, Shigella limits STING signaling through IpaJ and VirA proteins to promote its growth [90]. …”

Exploitation of the host cell ubiquitin machinery by microbial effector proteins

“…IpaH4.5 directly interacts with and mediates the ubiquitylation and degradation of the NF-κB protein subunit p65 (also known as RelA) . Moreover, IpaH4.5 has been shown to ubiquitylate TANKbinding kinase 1 (TBK1) to inhibit IFN regulatory factor 3 (IRF3)-mediated cytokine activation and the host antibacterial response (Zheng et al, 2016). IpaH1.4 and its homolog IpaH2.5, ubiquitylate HOIP (also known as RNF31), the catalytic component of the linear ubiquitin chain assembly complex (LUBAC) (de Jong et al, 2016).…”