Mycobacterium tuberculosis Uses Mce Proteins to Interfere With Host Cell Signaling.

Tuberculosis continues to be the main cause for mortality by an infectious agent, making Mycobacterium tuberculosis one of the most successful pathogens to survive for long durations within human cells. In order to survive against host defenses, M. tuberculosis modulates host cell signaling. It employs many proteins to achieve this and the Mce proteins are emerging as one group that play a role in host cell signaling in addition to their primary role as lipid/sterol transporters. Mce proteins belong to the conserved Mce/MlaD superfamily ubiquitous in diderm bacteria and chloroplasts. In mycobacteria, mce operons, encode for six different Mce proteins that assemble with inner membrane permeases into complexes that span across the mycobacterial cell wall. Their involvement in signaling modulation is varied and they have been shown to bind ERK1/2 to alter host cytokine expression; eEF1A1 to promote host cell proliferation and integrins for host cell adherence and entry. Recently, structures of prokaryotic Mce/MlaD proteins have been determined, giving an insight into the conserved domain. In this mini-review, we discuss current evidence for the role of mycobacterial Mce proteins in host cell signaling and structural characteristics of the protein-protein interactions coordinated by the human proteins to modulate the host signaling.

Impact of insulin signaling and proteasomal activity on physiological output of a neuronal circuit in aging Drosophila melanogaster.

The insulin family of growth factors plays an important role in development and function of the nervous system. Reduced insulin and insulin-growth-factor signaling (IIS), however, can improve symptoms of neurodegenerative diseases in laboratory model organisms and protect against age-associated decline in neuronal function. Recently, we showed that chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber escape response circuit. Here, we expand our initial findings by demonstrating that reduced functional output in the giant fiber system of aging flies can be prevented by increasing proteasomal activity within the circuit. Manipulations of IIS in neurons can also affect longevity, underscoring the relevance of the nervous system for aging.

Reduced insulin signaling maintains electrical transmission in a neural circuit in aging flies.

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the "insulin paradox"). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.

The development of novel LTA4H modulators to selectively target LTB4 generation.

The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.