Vincenz L et al. (2014) Cell "Sugarcoating ER Stress."

Vincenz L, Hartl FU

[Cell, 2014]

The hexosamine biosynthetic pathway (HBP) generates metabolites for protein N- and O-glycosylation. Wang et al. and Denzel et al. report a hitherto unknown link between the HBP and stress in the endoplasmic reticulum. These studies establish the HBP as a critical component of the cellular machinery of protein homeostasis.

Matsumoto M et al. (2005) Cell Metab "All roads lead to FoxO."

Accili D, Matsumoto M

[Cell Metab, 2005]

Stress-activated kinases control metabolism by antagonizing the early steps of insulin signal transduction. Two papers now demonstrate that Jnk, the prototypical stress-activated kinase, controls life span in Drosophila and C. elegans by promoting phosphorylation of the forkhead protein FoxO (Oh et al., 2005; Wang et al., 2005). The findings provide yet another mechanism by which metabolic and stress responses are integrated via phosphorylation of FoxO proteins.

Labouesse M (2015) Dev Cell "Adhesion with a Sumo."

Labouesse M

[Dev Cell, 2015]

Adherens junctions (AJs) play a crucial role in epithelial tissue development and tumorigenesis, and the mechanisms controlling their assembly and disassembly have therefore attracted considerable attention. A paper from Tsur et al. (2015) in this issue of Developmental Cell now shows how sumoylation and desumoylation of E-cadherin promotes its recruitment to AJs.

Storelli G et al. (2013) Cell Metab "Metformin, microbes, and aging."

Leulier M, Storelli G, Tefit M

[Cell Metab, 2013]

The mechanisms underlying the biological activity of metformin, a widely prescribed drug to treat type 2 diabetes, remain elusive. In a recent issue of Cell, Cabreiro et al. report that in C. elegans, metformin indirectly impacts lifespan by altering the methionine metabolism of its microbial partner E. coli (Cabreiro et al., 2013).

Nguyen TP et al. (2012) BMC Biol "Folate status of gut microbiome affects Caenorhabditis elegans lifespan."

Clarke CF, Nguyen TP

[BMC Biol, 2012]

In a paper in BMC Biology Virk et al. show that Caenorhabditis elegans lifespan is extended in response to a diet of folate-deficient Escherichia coli. The deficiencies in folate biosynthesis were due to an aroD mutation, or treatment of E. coli with sulfa drugs, which are mimics of the folate precursor para-aminobenzoic acid. This study suggests that pharmacological manipulation of the gut microbiome folate status may be a viable approach to slow animal aging, and raises questions about folate supplementation.

Garsin DA et al. (2013) Gut Microbes "Candida albicans and Enterococcus faecalis in the gut: synergy in commensalism?"

Garsin DA, Lorenz MC

[Gut Microbes, 2013]

The fungus Candida albicans and the gram-positive bacterium Enterococcus faecalis are both normal residents of the human gut microbiome and cause opportunistic disseminated infections in immunocompromised individuals. Using a nematode infection model, we recently showed that co-infection resulted in less pathology and less mortality than infection with either species alone and this was partly explained by an interkingdom signaling event in which a bacterial-derived product inhibits hyphal morphogenesis of C. albicans. In this addendum we discuss these findings in the contest of other described bacterial-fungal interactions and recent data suggesting a potentially synergistic relationship between these two species in the mouse gut as well. We suggest that E. faecalis and C. albicans promote a mutually beneficial association with the host, in effect choosing a commensal lifestyle over a pathogenic one.

Nurrish S (2014) Genetics "Dense core vesicle release: controlling the where as well as the when."

Nurrish S

[Genetics, 2014]

Ca(2+)/calmodulin-dependent Kinase II (CaMKII) is a calcium-regulated serine threonine kinase whose functions include regulation of synaptic activity (Coultrap and Bayer 2012). A postsynaptic role for CaMKII in triggering long-lasting changes in synaptic activity at some synapses has been established, although the relevant downstream targets remain to be defined (Nicoll and Roche 2013). A presynaptic role for CaMKII in regulating synaptic activity is less clear with evidence for CaMKII either increasing or decreasing release of neurotransmitter from synaptic vesicles (SVs) (Wang 2008). In this issue Hoover et al. (2014) further expand upon the role of CaMKII in presynaptic cells by demonstrating a role in regulating another form of neuronal signaling, that of dense core vesicles (DCVs), whose contents can include neuropeptides and insulin-related peptides, as well as other neuromodulators such as serotonin and dopamine (Michael et al. 2006). Intriguingly, Hoover et al. (2014) demonstrate that active CaMKII is required cell autonomously to prevent premature release of DCVs after they bud from the Golgi in the soma and before they are trafficked to their release sites in the axon. This role of CaMKII requires it to have kinase activity as well as an activating calcium signal released from internal ER stores via the ryanodine receptor. Not only does this represent a novel function for CaMKII but also it offers new insights into how DCVs are regulated. Compared to SVs we know much less about how DCVs are trafficked, docked, and primed for release. This is despite the fact that neuropeptides are major regulators of human brain function, including mood, anxiety, and social interactions (Garrison et al. 2012; Kormos and Gaszner 2013; Walker and Mcglone 2013). This is supported by studies showing mutations in genes for DCV regulators or cargoes are associated with human mental disorders (Sadakata and Furuichi 2009; Alldredge 2010; Quinn 2013; Quinn et al. 2013). We lack even a basic understanding of DCV function, such as, are there defined DCV docking sites and, if so, how are DCVs delivered to these release sites? These results from Hoover et al. (2014) promise to be a starting point in answering some of these questions.

Sewell AK et al. (2018) Microb Cell "An unexpected benefit from E. coli: how enterobactin benefits host health."

Qi B, Han M, Sewell AK

[Microb Cell, 2018]

Iron plays many critical roles in human biology, such as aiding the transport of oxygen and mediating redox reactions. Iron is essential for life, yet little is known about how iron is taken up into mitochondria to impact the labile iron pool. Iron deficiency is one of the most prevalent human nutrient-deficiency diseases in the world and is a major cause of anemia that affects &gt;25% of the world's population, but unfortunately the current treatment (oral iron supplementation) is inefficient and has many side effects. A greater understanding of iron uptake, and discovery of molecules that aid in this process, may lead to more effective treatments for iron deficiency. In this study, we uncovered a unique and surprising role for an <i>Escherichia coli</i>-produced siderophore enterobactin (Ent) that facilitates iron uptake by the host, observed in both <i>C. elegans</i> and mammalian cells. Although siderophores are well-known Fe⁺³ scavengers, this activity has previously been described to only benefit iron acquisition by bacteria, not the host. This unexpected function is dependent on the binding of Ent to the host's ATP synthase -subunit but is independent of other subunits of the ATP synthase. This finding marks a major shift regarding the role of this siderophore in the &quot;iron tug-of-war&quot; paradigm, which is often used to describe the fight between the bacteria and the host for this essential micronutrient. Instead, this study presents <i>E. coli</i> as a commensal &quot;friend&quot; that provides a molecule that supports the host's iron homeostasis. This work reveals a novel, beneficial role of a bacteria-generated molecule in aiding the host's iron homeostasis, and points to surprising new benefits from commensal bacteria.