Salmonella Enteritidis Effector AvrA Suppresses Autophagy by Reducing Beclin-1 Protein

Abstract

Autophagy is a cellular process to clear pathogens. Salmonella enterica serovar Enteritidis (S.E) has emerged as one of the most important food-borne pathogens. However, major studies still focus on Salmonella enterica serovar Typhimurium. Here, we reported that AvrA, a S. Enteritidis effector, inhibited autophagy to promote bacterial survival in the host. We found that AvrA regulates the conversion of LC3 I into LC3 II and the enrichment of lysosomes. Beclin-1, a key molecular regulator of autophagy, was decreased after AvrA expressed strain colonization. In S.E-AvrA − -infected cells, we found the increases of protein levels of p-JNK and p-c-Jun and the transcription level of AP-1. AvrA-reduction of Beclin-1 protein expression is through the JNK pathway. The JNK inhibitor abolished the AvrA-reduced Beclin-1 protein expression. Moreover, we identified that the AvrA mutation C186A abolished its regulation of Beclin-1 expression. In addition AvrA protein was found interacted with Beclin-1. In organoids and infected mice, we explored the physiologically related effects and mechanism of AvrA in reducing Beclin-1 through the JNK pathway, thus attenuating autophagic responses. This finding not only indicates an important role of S. Enteritidis effector in reducing host protein as a strategy to suppress autophagy, but also suggests manipulating autophagy as a new strategy to treat infectious diseases.

Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer

“…Autophagy is a catabolic process in which autophagosomes is formed, and it has double-sided effect in cancer proliferation and death [21,22]. LC3 and Beclin-1 are key molecular regulator of autophagy and can be used as autophagy marker [23,24]. To investigate whether CYT997 could trigger autophagy in GC cells, Lyso-Tracker Red, a membrane acidotropic dye probe was used to mark cellular acidic organelles (AVOs), such as lysosomes and autolysosomes.…”

Salmonella spvC Gene Inhibits Autophagy of Host Cells and Suppresses NLRP3 as Well as NLRC4

“…Autophagy is an important component of the innate immune system in host anti-bacterial defense, which is known to target a population of Salmonella for degradation and restrict Salmonella replication (27,28). Beclin 1 interacts with several cofactors (e.g., Atg14L, HMGB1, IP3R and PINK) to promote the formation of Beclin 1-Vps34-Vps15 core complexes, thereby inducing autophagy (9). LC3, a mammalian homolog of yeast Atg8, is known to serve as a widely used marker for autophagosomes.…”

“…But the pathogens have developed several survival mechanisms to prevent this degradation event (7). S. Typhimurium, including its effectors, has evolved to block host signaling cascades or even create favorable conditions for self-replication and survival by virtue of autophagy through specific mechanisms, so as to resist the host defense (8,9). It has been reported that spvC is responsible for the anti-inflammatory effect of S. Typhimurium to facilitate bacterial dissemination, and the host can eliminate intracellular bacteria by autophagy, which can inhibit the further spread of bacteria.…”

AvrA Exerts Inhibition of NF-κB Pathway in Its Naïve Salmonella Serotype through Suppression of p-JNK and Beclin-1 Molecules

“…Although Beclin-1 is a key regulator for autophagy and apoptosis, activation of autophagy induces an increased expression of the anti-inflammatory cytokine IL-10 and decreases the expression of IL-8 and TNF-α [ 21 ]. It is reported that S. Enteritidis AvrA inhibits autophagic response by decreasing the Beclin-1 concentration, which may be associated with the JNK/AP-1 signaling pathway [ 22 ]. In our study, deficiency of SP-AvrA in S. Pullorum C79-13 caused the upregulation of Beclin-1 and p-JNK in infected HeLa and Caco2 BBE cells, suggesting that SP-AvrA may control autophagy in the anti-inflammatory response.…”