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Toll-like receptors (TLRs) are important sentinels of bacterial and viral infection and thus fulfil a critical sensory role in innate immunity. Polo-like kinases (PLKs), a five membered family of Ser/Thr protein kinases, have long been studied for their role in mitosis and thus represent attractive therapeutic targets in cancer therapy. Recently, PLKs were implicated in TLR signaling in mice but the role of PLKs in TLR signaling in untransformed primary immune cells has not been addressed, even though PLK inhibitors are in clinical trials. We here identified several phospho-serine and phospho-threonine residues in the known TLR pathway kinases, Interleukin-1 receptor-associated kinase (IRAK) 2 and IRAK4. These sites lie in canonical polo-box motifs (PBM), sequence motifs known to direct recruitment of PLKs to client proteins. Interestingly, PLK1 was phosphorylated and PLK 2 and 3 mRNA induced upon TLR stimulation in primary immune cells, respectively. In whole blood, PLK inhibition disparately affected TLR mediated cytokine responses in a donor- and inhibitor-dependent fashion. Collectively, PLKs may thus potentially interface with TLR signaling in humans. We propose that temporary PLK inhibitor-mediated blockade of TLR-signaling in certain patients receiving such inhibitors during cancer treatment may cause adverse effects such as an increased risk of infections due to a then compromised ability of the TLR recognition system to sense and initiate cytokine responses to invading microbes.

Cells infected with Salmonella are characterised by the appearance of membrane tubular structures that stretch from the bacterial vacuole. The formation of these tubules requires the translocation of Salmonella effector proteins within the infected cell. Different types of Salmonella-induced tubules with varying host protein compositions have been identified. This variability probably reflects the ability of these tubules to interact with different host compartments. Membrane tubules decorated with effector proteins but essentially devoid of host proteins and named LAMP1-negative (LNT) were observed. LNTs wrap around LAMP1-positive vesicles and may promote recruitment of lysosomal glycoproteins to bacterial vacuole and the formation of a replication niche. We conducted a biochemical and functional characterisation of LNTs. We show that the effector proteins SseF and SseG are necessary for their formation. The absence of these tubules is associated with decreased recruitment of LAMP1 to SCVs, decreased intracellular replication of Salmonella, and decreased virulence in mice. We found that the process leading to the recruitment of lysosomal glycoproteins to tubules involves the C-terminal domain of the effector protein SifA and the GTPase Arl8b. Overall, these data suggest that Salmonella-induced tubules promote the establishment of the replication niche by promoting recruitment of host proteins to the bacterial vacuole., (© 2018 John Wiley & Sons Ltd.)