T-cell activation is mediated by antigen-specific signals from the TCRζ/CD3 and CD4–CD8–p56lck complexes in combination with additional co-signals provided by coreceptors such as CD28, inducible costimulator (ICOS), cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death (PD-1), and others. CD28 and ICOS provide positive signals that promote and sustain T-cell responses, while CTLA-4 and PD-1 limit responses. The balance between stimulatory and inhibitory co-signals determines the ultimate nature of T-cell responses where response to foreign pathogen is achieved without excess inflammation and autoimmunity. In this review, we outline the current knowledge of the CD28 and CTLA-4 signaling mechanisms [involving phosphatidylinositol 3 kinase (PI3K), growth factor receptor-bound protein 2 (Grb2), Filamin A, protein kinase C θ (PKCθ), and phosphatases] that control T-cell immunity. We also present recent findings on T-cell receptor-interacting molecule (TRIM) regulation of CTLA-4 surface expression, and a signaling pathway involving CTLA-4 activation of PI3K and protein kinase B (PKB)/AKT by which cell survival is ensured under conditions of anergy induction.

CD28 and CTLA-4 coreceptor expression and signal transduction.

Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy.

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Choline metabolism in malignant transformation

Phosphatidylinositol 4 Phosphate Regulates Targeting of Clathrin Adaptor AP-1 Complexes to the Golgi

Secretory granules are specialized intracellular organelles that serve as a storage pool for selected secretory products. The exocytosis of secretory granules is markedly amplified under physiologically stimulated conditions. While granules have been recognized as post-Golgi carriers for almost 40 years, the molecular mechanisms involved in their formation from the trans-Golgi network are only beginning to be defined. This review summarizes and evaluates current information about how secretory proteins are thought to be sorted for the regulated secretory pathway and how these activities are positioned with respect to other post-Golgi sorting events that must occur in parallel. In the first half of the review, the emerging role of immature secretory granules in protein sorting is highlighted. The second half of the review summarizes what is known about the composition of granule membranes. The numerous similarities and relatively limited differences identified between granule membranes and other vesicular carriers that convey products to and from the plasmalemma, serve as a basis for examining how granule membrane composition might be established and how its unique functions interface with general post-Golgi membrane traffic. Studies of granule formation in vitro offer additional new insights, but also important challenges for future efforts to understand how regulated secretory pathways are constructed and maintained.

Sorting and storage during secretory granule biogenesis: looking backward and looking forward.

Signaling roles for phosphoinositides that involve their regulated hydrolysis to generate second messengers have been well characterized. Recent work has revealed additional signaling roles for phosphoinositides that do not involve their hydrolysis. PtdIns 3-P, PtdIns 3,4,5-P3, and PtdIns 4,5-P2 function as site-specific signals on membranes that recruit and/or activate proteins for the assembly of spatially localized functional complexes. A large number of phosphoinositide-binding proteins have been identified as the potential effectors for phosphoinositide signals. Common themes of localized signal generation and the spatially localized recruitment of effector proteins appear to underlie mechanisms employed in signal transduction, cytoskeletal, and membrane trafficking events.

PHOSPHOINOSITIDE LIPIDS AS SIGNALING MOLECULES: Common Themes for Signal Transduction, Cytoskeletal Regulation, and Membrane Trafficking

Nodulin proteins are expressed in legume root cells after infection with rhizobia. Nodulins have been classified as early and late, reflecting the developmental time points of their expression. Leghemoglobin (LegH), which is a classical example of a late nodulin, sequesters oxygen inside the nodule to protect the nitrogenase from oxygen toxicity to sustain symbiotic nitrogen fixation (SNF). Post-translational modification and/or protein–protein interaction are known to regulate activity of proteins. To elucidate the role of post-translational modification of LegH on its oxygen sequestration activity, earlier we have shown that phosphorylation at its S45 imparts most structural disruption of the porphyrin binding pocket responsible for its oxygen binding. In the present report, in an attempt to characterize the protein(s) that may interact with LegH to regulate its activity, it is demonstrated that LegH interact in vitro with Nodulin 16 of Lotus japonicus (Nlj16), another late nodulin. These two interacting proteins resulted in a bigger sized particle which shows higher diffusion coefficient as measured by dynamic light scattering. Interestingly, it was also shown that in vitro oxygen sequestration by LegH is stimulated by this interaction. Furthermore, this interaction is validated by the fact that LegH and Nlj16 could be co-immunoprecipitated from the nodule lysate. Most importantly, fluorescent immunohistochemistry of post-infected nodule sections show perceivable co-localization of these two proteins in the nodule symbiosomes. Thus, this work is a foundation for further investigation on these two interacting late nodulins as one of the plausible regulations for the oxygen sequestration by LegH during SNF.

Oxygen sequestration by Leghemoglobin is positively regulated via its interaction with another late nodulin, Nlj16 of Lotus japonicus

Nitrogenase that catalyses anaerobic symbiotic nitrogen fixation (SNF) in legumes is synthesized by rhizobium. Legume root cells express nodulin proteins after infection with rhizobia. Nodulins have been classified as early and late, reflecting the time points of their expression. Leghemoglobin (LegH), which is a classic example of a late nodulin, sequesters oxygen inside the nodule to protect the nitrogenase from oxygen toxicity to sustain SNF. Previous data from our laboratory demonstrated that phosphorylated LegH at S45 showed compromised oxygen sequestration in vitro due to structural disruption of the porphyrin binding pocket responsible for its oxygen binding. Moreover, we have demonstrated by using co-immunoprecipitation that LegH interacts both in vitro with Nodulin 16 of Lotus japonicus (Nlj16), another late nodulin. Fluorescence Immunohistochemistry (IHC) data shows that both LegH and Nlj16 are localized in the membrane and cytosol of infected cells. Notably, serine phosphorylation of LegH and interaction of Nlj16 with LegH respectively reduces and increases its in vitro oxygen sequestration ability. In this report, to further elucidate the spatio-temporal regulation of this interaction, we generated hairy root transgenic Lotus japonicus plants where Nlj16 has been knocked down by using siRNA. Most interestingly, our data shows that the membrane localization of LegH is obliterated in the Nlj16 knocked-down root cells infected with the cognate Rhizobia suggesting a distinct role of Nlj16 in its recruitment to the membrane of nodule cells.

Nodulin 16 of Lotus japonicus (Nlj16) regulates the recruitment of Leghemoglobin (LegH) to the infected nodule cell membrane during symbiotic nitrogen fixation

Frb Domain of Human Tor Protein Induces Compromised Proliferation Andmitochondrial Dysfunction in L. Donovani Promastigotes

FRB domain of human TOR protein induces compromised proliferation and mitochondrial dysfunction in Labrus donovani promastigotes.

Tyrosine Phosphorylation of Downstream of Kinase 3 (Dok-3) Plays Crucial Role in Leishmania Donovani Infection by Regulating Inhibitory Proteins, SH-PTP-1 and SHIP-1 in Macrophages

Anirban Siddhanta

Papers

Oxygen sequestration by Leghemoglobin is positively regulated via its interaction with another late nodulin, Nlj16 of Lotus japonicus

Nodulin 16 of Lotus japonicus (Nlj16) regulates the recruitment of Leghemoglobin (LegH) to the infected nodule cell membrane during symbiotic nitrogen fixation

Frb Domain of Human Tor Protein Induces Compromised Proliferation Andmitochondrial Dysfunction in L. Donovani Promastigotes

FRB domain of human TOR protein induces compromised proliferation and mitochondrial dysfunction in Labrus donovani promastigotes.

Tyrosine Phosphorylation of Downstream of Kinase 3 (Dok-3) Plays Crucial Role in Leishmania Donovani Infection by Regulating Inhibitory Proteins, SH-PTP-1 and SHIP-1 in Macrophages