The late endosomal adaptor p14 is a macrophage host defense factor against Salmonella Typhimurium infection

Abstract

SummaryThe outcome of an infection depends on the balance between host resistance and bacterial virulence. Here, we show that the late endosomal adaptor p14 (also known as LAMTOR2) is one of the components for cellular host defense against the intracellular pathogen Salmonella enterica serovar Typhimurium. During Salmonella infection, the complex of p14 and MP1 is required for the accurately timed transport of Salmonella through the endolysosomal system. Loss of p14 opens a time window that allows Salmonella to populate a replication niche, in which early and late antimicrobial effector systems, comprising NADPH phagocytic oxidase and inducible nitric oxide synthase, respectively, are inappropriately activated. Thus, p14 supports the accurate transport of Salmonella through the endolysosomal system, thereby limiting bacterial replication in both, professional phagocytes and in non-phagocytic cells in vitro, and helps mice to successfully battle Salmonella infection in vivo.

LAMTOR2 regulates dendritic cell homeostasis through FLT3-dependent mTOR signalling

“…LAMTOR2 plays a critical role in tissue homeostasis and immunity10111227. Here, we contribute insights into the function of LAMTOR2, as part of the Ragulator/LAMTOR complex, which operates as molecular switch on the late endosome to differentially regulate mTOR and MAPK-signalling downstream of the Flt3-receptor.…”

“…They suffer from neutropenia, defects in T-cell function and B-cell maturation and subsequently have recurrent broncho-pulmonary infections11. In correlation with these observations, we could recently show in a mouse model that LAMTOR2 is crucial for macrophages to fight Salmonella infection by controlling replication in the phagosome12. Based on these findings, we were interested in the role of LAMTOR2 for adaptive immunity.…”

The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis

“…The adaptor molecule p14 has been shown to contribute to ERK as well as mTORC1 signaling in nonimmune 6,9,10,12 and also immune cells. 1,14 It has been shown previously that p14 depletion significantly affects protein stability of all other LAMTOR components and thereby also mTORC1 and MAPK signaling. 9,31 Here, we have extended these observations toward DCs.…”

“…About 70% to 80% of CD11c 1 BMDCs were positive for tdTomato and were thus considered to have deleted p14 ( Figure 7B). Based on previous reports showing that p14 depletion affects MAPK signaling in nonimmune 12 and immune cells, 14 we analyzed the activation of the classical MAPK effector kinases ERK1/2, c-Jun N-terminal kinase (JNK), and p38. We noticed significantly decreased activity of ERK1 and 2 in p14-deficient BMDCs.…”

“…[6][7][8][9][10][11] Furthermore, p14 critically participates in the regulation of endosomal trafficking, growth factor signaling (eg, epidermal growth factor [EGF] receptor), and cell proliferation. [12][13][14] The role of p14 in such fundamental cellular and immunologic processes 1,14 raised our interest to elucidate its function in dendritic cells (DCs), the key antigen-presenting cells of the mammalian organism. 15 The skin represents a major entry site for pathogens as well as a target organ for vaccine delivery.…”