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Interferon signaling prompts the expression of interferon-stimulated genes ISGs which encode a wide range of antimicrobial proteins 2. Vertebrate GBPs contribute to defense against diverse pathogens, and GBP function has also been implicated in the regulation of inflammation 3 , — 5. GBPs consist of an N-terminal catalytic GTPase domain followed by an elongated helical domain which mediates interactions with target proteins or membranes.

GTP binding and hydrolysis promote the dimerization, oligomerization, and polymerization of GBPs as well as recruitment of additional GBP family members 6. Oligomerization of GBPs on pathogen-containing membrane-bound compartments prompts an array of antimicrobial activities, including the production of radical oxygen species by corecruited oxidases, the fusion of these compartments with degradative lysosomes, their encapsulation within autophagosome-like structures, and the lytic disintegration of microbe-containing compartments 7.

Some GBPs also possess the ability to target microbes that reside inside the host cell cytosol. Cytosolic bacteria enclosed by GBPs undergo lytic destruction in mouse macrophages 8 , — 10 or are blocked from engaging the host actin polymerization machinery in human epithelial cells, thereby losing the ability to disseminate 11 , The importance of GBPs as potent immune effectors is further illustrated by the recent discovery that the enteric bacterial pathogen Shigella flexneri injects host cells with the virulence factor IpaH9.

While IpaH9. Despite a wealth of evidence supporting the idea of a role of GBPs in cell-autonomous host defense, the molecular mechanisms underlying GBP function and target specificity remain enigmatic. In particular, GBP1, GBP2, and GBP5 in humans are predicted to directly associate with target membranes due to the presence of a C-terminal CaaX box leading to posttranslational prenylation, which acts as a hydrophobic lipid anchor 6. In support of this model, it was previously shown that recombinant human GBP1 hGBP1 binds directly to lipid bilayers in vitro in a GTP- and prenylation-dependent manner Consistent with this hypothesis, we previously demonstrated that hGBP1 is unique among all human GBPs in its ability to target cytosolic S.

The unique ability of hGBP1 among all human GBPs to target cytosolic Gram-negative bacteria, the expansion of the GBP gene family in humans and other species, and the diversity of targets recognized by distinct GBP isoforms suggest a model in which individual GBPs have evolved unique characteristics to recognize and respond to pathogens spanning the entire tree of life. It is also notable that mouse Gbp2, the closest murine homolog of hGBP1, lacks a clearly defined C-terminal PBM and yet is capable of recognizing and eliminating cytosolic S.

Collectively, these findings suggest that the divergence of GBPs within and between host genomes has drastically shifted bacterial recognition function, potentially in response to antagonistic coevolution with pathogens. In the current study, we set out to address this issue, focusing on a subset of primate GBPs which possess the ability to specifically recognize and bind cytosolic bacteria. Thus, understanding PIN polarity and activity control at the plasma membrane can substantially contribute to the understanding of plant growth.

PIN-mediated auxin transport is critically dependent on phosphorylation by protein kinases Barbosa and Schwechheimer, Conversely, pharmacological interference with D6PK abundance at the plasma membrane impairs auxin transport-dependent tropic responses Barbosa et al. Although both D6PK and PINs are polarly localized at the plasma membranes of cells of different plant tissues, their recycling kinetics are dramatically different and obviously mediated by different trafficking pathways Barbosa et al.

Understanding how D6PK associates with the plasma membrane is thus important for understanding D6PK-mediated auxin transport and plant growth regulation. Peripheral membrane proteins can be anchored to membranes by diverse mechanisms that include protein-protein and protein-lipid interactions Cho and Stahelin, The very low abundant phosphoinositides PIs are important players for the recruitment of peripheral proteins to membranes Balla, ; Heilmann, PIs are mono-, bis- and tris-phosphorylated derivatives of phosphatidylinositol PtdIns and PI compositions differ between the plasma membrane and different organellar membranes Balla, Membrane-specific PI distribution, a result of the differential distribution and tight regulation of specific PI kinases or phosphatases, allows recruiting specific cognate binding proteins that determine organelle function Behnia and Munro, In particular, asymmetric PI distribution in the plasma membrane contributes to the organization of polar domains in many organisms and biological processes Comer and Parent, ; McCaffrey and Macara, ; Orlando and Guo, ; Shewan et al.

In plants, the polar distribution of PIs, PI kinases, PI binding partners and associated processes are extensively studied in tip growing cells such as pollen tubes and root hairs Kusano et al. More recently, PtdIns4P was identified as a major PI, conferring negative charges to the plant plasma membrane Simon et al.

Peripheral membrane proteins can bind PIs through globular PI species-specific binding domains, e. Alternatively, peripheral membrane proteins can bind membranes through ionic interactions between stretches of positively charged basic amino acids [lysine K or arginine R ] and the negatively charged lipids, such as PIs or PtdOH phosphatidic acid Brzeska et al.

D6PK associates also with root hair tips following root hair initiation Stanislas et al. Here, we show that D6PK is able to bind phospholipids with polyacidic headgroups and that phospholipid composition critically determines D6PK plasma membrane recruitment and polarity. Thus, phospholipid-dependent recruitment of AGCVIII kinases through ionic interactions between the polyacidic phospholipid headgroups and polybasic motifs emerge as general control mechanisms of protein-membrane binding, and in the case of D6PK for auxin transport control.

D6PK did not bind to phospholipids with neutral headgroups, namely PtdCho phosphatidylcholine and PtdEtn phosphatidylethanolamine , or to phospholipids with monoacidic headgroups such as PtdIns and phosphatidylserine PtdSer; Fig. View large Download slide D6PK binds to polyacidic phospholipids. The experiment was repeated twice, one representative blot is shown. All samples from the upper panel are from the same blot; the blot was spliced to eliminate the marker lane dashed line.

PI biosynthesis begins with PtdIns and involves several phosphorylation and dephosphorylation steps by PI kinases and phosphatases Meijer and Munnik, For comparisons and to establish the effectiveness of the inhibitor treatments, we also analysed the localization of phosphoinositide-specific biosensors, PIN2:GFP trafficking and the uptake of the lipophylic dye and endocytosis tracer FM Fig. S1 Jaillais et al. View large Download slide Phosphoinositide and phosphatidic acid composition determine D6PK recruitment and polarity at the plasma membrane.

Black arrows, biosynthetic steps analysed in this study; grey arrows, biosynthetic steps that could not be selectively manipulated Simon et al. All treatments were performed for 30 min in liquid media: mock 0. C Plasma membrane PM dissociation index determined as the ratio between the signal detected in the cytosol solid line in inset image and at the basal plasma membrane dashed line in inset image.

S, soluble supernatant; M, membrane pellet, after , g centrifugation. The experiment was repeated with similar outcomes using three biological replicates. The semi-quantitative colour-coded heatmap for signal intensities also applies to B. S1 Li and Xue, Thus, the reported alterations of PtdIns 4,5 P2 levels in pip5k1 pip5k2 mutants might exert an influence on the plasma membrane targeting of D6PK Ischebeck et al. In addition, the kinase domains are flanked by N- and C-terminal domains of to amino acids and 45 to 57 amino acids, respectively Fig.

The deletion of any of the three domains resulted in the loss of the plasma membrane association of D6PK Fig. Regardless, each of these deletion variants remained associated with membranes, possibly endomembranes Fig. Thus, the MID domain is sufficient to mediate the plasma membrane association of D6PK, and to some extent also its polar distribution, but all three domains are required for D6PK plasma membrane association.