Integrated control of protein degradation in C. elegansmuscle
Protein degradation is a fundamental cellular process, the genomic control of which is incompletely understood. The advent of transgene-coded reporter proteins has enabled the development of C. elegans into a model for studying this problem. The regulation of muscle protein degradation is surprisingly complex, integrating multiple signals from hypodermis, intestine, neurons and muscle itself. Within the muscle, degradation is executed by separately regulated autophagy-lysosomal, ubiquitin-proteasome and calpain-mediated systems. The signal-transduction mechanisms, in some instances, involve modules previously identified for their roles in developmental processes, repurposed in terminally differentiated muscle to regulate the activities of pre-formed proteins. Here we review the genes, and mechanisms, which appear to coordinately control protein degradation within C. elegans muscle. We also consider these mechanisms in the context of development, physiology, pathophysiology and disease models.
A seminal fluid protease activates sperm motility in C. elegans males
Seminal fluid factors have been shown to play a significant role in fertility in many animals. However, little is known about the contributions of seminal fluid to male fertility in C. elegans. In this commentary, we summarize our recent finding of a seminal fluid sperm activator, the serine protease TRY-5. TRY-5 is required for males to activate sperm, yet surprisingly it is not required for male fertility, likely due to redundancy with an activator present in hermaphrodites. TRY-5 is transferred to hermaphrodites during mating in a series of distinct release events just prior to transfer of sperm. Thus, we propose a model in which TRY-5 cleaves sperm cell surface proteins to trigger sperm maturation. We discuss other possible roles for seminal fluid factors in C. elegans and prospects for using TRY-5 as a marker for studies of male mating behavior and seminal fluid secretion.
Regulation of tubulin glutamylation plays cell-specific roles in the function and stability of sensory cilia
Microtubules (MTs) are post-translationally modified, but the functions of post-translational modifications (PTMs) have in many cases remained unknown. Most PTMs, such as polyglutamylation, occur on the protruding C-terminal tail (CTT) of tubulins, are reversible, and have been proposed to play a role in regulation of MT-associated proteins (MAPs), molecular motors, and MT-severing proteins. Several PTM enzymes have been identified, including a carboxypeptidase in mice known as CCP1, which reduces polyglutamylation on the CTT of MTs, and causes cell-specific neurodegeneration when mutated.
Speculations on the activation of ROS generation in C. elegans innate immune signaling
We recently published work demonstrating that ROS (reactive oxygen species) generated by the dual oxidase, Ce-Duox1/BLI-3, in response to infection in Caenorhabditis elegans activates the transcription factor SKN-1, initiating a protective response. Moreover, we showed that the crucial innate immune pathway, p38 MAPK signaling, was responsible for relaying the activating signal. In this commentary, we speculate on the signaling pathway upstream of Ce-Duox1/BLI-3 that triggers its activity. Specifically, we hypothesize that a G-protein signaling pathway comprising Gαq - PLCβ - TPA-1 - DKF-2 activates Ce-Duox1/BLI-3. Our rationale is based on work showing that these components are connected to p38 MAPK signaling and innate immunity in the worm, and investigations in other organisms demonstrating that some of these components are involved in dual oxidase activation.
One hundred and sixty five years have passed since the first documented use of volatile anesthetics to aid in surgery, but we have yet to understand the underlying mechanism of action of these drugs. There is no question that, in vitro, volatile anesthetics can affect the function of numerous neuronal and non-neuronal proteins. In fact, volatile anesthetics are capable of binding such diverse proteins as albumin and bacterial luciferase. The promiscuity of volatile anesthetic binding makes it difficult to determine which proteins are modulated by anesthetics to cause the state of anesthesia. Consequently, despite a great deal of in vitro data, the fundamental physiological process that volatile anesthetics perturb to effect neuronal silencing is not yet identified. Recently, data has increasingly indicated that membrane leak channels may play a role in the anesthetic response. Here we comment on the use of optogenetics to further support such a model.
The transcription factor VAB-23 links vulval cell fate specification and morphogenesis
During organogenesis, individual cells must commit to and execute specific cell fates. However, the molecular mechanisms linking cell fate specification to fate execution and morphogenesis remain a largely unexplored area in developmental biology. The Caenorhabditis elegans vulva is an excellent model to dissect the molecular pathways linking cell fate specification and execution during organogenesis. We have recently identified a conserved nuclear zinc finger transcription factor called VAB-23 that plays essential roles during vulval torid formation in the larva and ventral epidermal closure in the embryo. VAB-23 regulates the transcription of specific target genes including smp-1 Semaphorin. EGFR/RAS/MAPK signaling upregulates via the HOX protein LIN-39 the expression of VAB-23 in the 1° vulval cell lineage, indicating that cell fate specification and execution are temporally overlapping and tightly linked processes. Here, we discuss the roles of VAB-23 in morphogenesis and the implications of its regulation on the spatio-temporal control of organogenesis.
Necrotic cell death and neurodegeneration: The involvement of endocytosis and intracellular trafficking
Necrosis, one of the two main types of cell death, contributes critically in many devastating pathological conditions in human, including stroke, ischemia, trauma and neurodegenerative diseases. However, unlike apoptosis, the molecular mechanisms underlying necrotic cell death and neurodegeneration are poorly understood. Caenorhabditis elegans offers a powerful platform for a thorough and systematic dissection of the molecular basis of necrotic cell death. Similarly to humans, neuronal necrosis can be induced by several well-characterized genetic lesions and by adverse environmental conditions in the nematode. The availability of precisely-defined C. elegans neurodegeneration models provides a unique opportunity for comprehensive delineation of the cellular and molecular mechanisms mediating necrotic cell death. Through genetic dissection of such models, we recently uncovered an unexpected requirement for specific proteins involved in endocytosis and intracellular trafficking, in the execution of necrosis. Moreover, initiation of necrotic cell death is accompanied by a sharp increase in the formation of early and recycling endosomes, which subsequently disintegrate during the final stage of cell death. These findings implicate endocytic and intracellular trafficking processes in the cellular destruction during necrosis. Indeed, endocytosis synergizes with two other essential cellular processes, autophagy and lysosomal proteolysis to facilitate necrotic neurodegeneration. In this commentary, we consider the contribution of endocytosis and intracellular trafficking to cell injury and discuss the crosstalk between these processes and other molecular mechanisms that mediate necrosis.
Most animals inhabit environments in which resources are heterogeneous and distributed in patches. A fundamental question in behavioral ecology is how an animal feeding on a particular food patch, and hence depleting it, decides when it is optimal to leave the patch in search of a richer one. Optimal foraging has been extensively studied and modeled in animals not amenable to molecular and neuronal manipulation. Recently, however, we and others have begun to elucidate at a mechanistic level how food patch leaving decisions are made. We found that C. elegans leaves food with increasing probability as food patches become depleted. Therefore, despite its artificial laboratory environment, its behavior conforms to the optimal foraging theory, which allowed us to genetically dissect the behavior. Here we expand our discussion on some of these findings, in particular how metabolism, oxygen and carbon dioxide regulate C. elegans food leaving behavior.