Ancient Function of Teneurins in Tissue Organization and Neuronal Guidance in the Nematode Caenorhabditis elegans

The nematode Caenorhabditis elegans expresses the ten-1 gene that encodes teneurin. TEN-1 protein is expressed throughout the life of C. elegans. The loss of ten-1 function results in embryonic and larval lethality, highlighting its importance for fundamental processes during development. TEN-1 is expressed in the epidermis and neurons. Defects in neuronal pathfinding and epidermal closure are characteristic of ten-1 loss-of-function mutations. The molecular mechanisms of TEN-1 function in neurite outgrowth, neuronal pathfinding, and dendritic morphology in C. elegans are largely unknown. Its genetic redundancy with the extracellular matrix receptors integrin and dystroglycan and genetic interactions with several basement membrane components suggest a role for TEN-1 in the maintenance of basement membrane integrity, which is essential for neuronal guidance. Identification of the lat-1 gene in C. elegans, which encodes latrophilin, as an interaction partner of ten-1 provides further mechanistic insights into TEN-1 function in neuronal development. However, receptor-ligand interactions between LAT-1 and TEN-1 remain to be experimentally proven. The present review discusses the function of teneurin in C. elegans, with a focus on its involvement in the formation of receptor signaling complexes and neuronal networks

Prefoldin Function in Cellular Protein Homeostasis and Human Diseases

Cellular functions are largely performed by proteins. Defects in the production, folding, or removal of proteins from the cell lead to perturbations in cellular functions that can result in pathological conditions for the organism. In cells, molecular chaperones are part of a network of surveillance mechanisms that maintains a functional proteome. Chaperones are involved in the folding of newly synthesized polypeptides and assist in refolding misfolded proteins and guiding proteins for degradation. The present review focuses on the molecular co-chaperone prefoldin. Its canonical function in eukaryotes involves the transfer of newly synthesized polypeptides of cytoskeletal proteins to the tailless complex polypeptide 1 ring complex (TRiC/CCT) chaperonin which assists folding of the polypeptide chain in an energy-dependent manner. The canonical function of prefoldin is well established, but recent research suggests its broader function in the maintenance of protein homeostasis under physiological and pathological conditions. Interestingly, non-canonical functions were identified for the prefoldin complex and also for its individual subunits. We discuss the latest findings on the prefoldin complex and its subunits in the regulation of transcription and proteasome-dependent protein degradation and its role in neurological diseases, cancer, viral infections and rare anomalies

Mitochondrial stress-dependent regulation of cellular protein synthesis

The production of newly synthesized proteins is vital for all cellular functions and is a determinant of cell growth and proliferation. The synthesis of polypeptide chains from mRNA molecules requires sophisticated machineries and mechanisms that need to be tightly regulated, and adjustable to current needs of the cell. Failures in the regulation of translation contribute to the loss of protein homeostasis, which can have deleterious effects on cellular function and organismal health. Unsurprisingly, the regulation of translation appears to be a crucial element in stress response mechanisms. This review provides an overview of mechanisms that modulate cytosolic protein synthesis upon cellular stress, with a focus on the attenuation of translation in response to mitochondrial stress. We then highlight links between mitochondrion-derived reactive oxygen species and the attenuation of reversible cytosolic translation through the oxidation of ribosomal proteins at their cysteine residues. We also discuss emerging concepts of how cellular mechanisms to stress are adapted, including the existence of alternative ribosomes and stress granules, and the regulation of co-translational import upon organelle stress

The Power in Groups: Using Cluster Analysis to Critically Quantify Women’s STEM Enrollment

Despite efforts to close the gender gap in science, technology, engineering, and math (STEM), disparities still exist, especially in math intensive STEM (MISTEM) majors. Females and males receive similar academic preparation and overall, perform similarly, yet females continue to enroll in STEM majors less frequently than men. In examining academic preparation, most research considers performance measures individually, ignoring the possible interrelationships between these measures. We address this problem by using hierarchical agglomerative clustering – a statistical technique which allows for identifying groups (i.e., clusters) of students who are similar in multiple factors. We first apply this technique to readily available institutional data to determine if we could identify distinct groups. Results illustrated that it was possible to identify nine unique groups. We then examined differences in STEM enrollment by group and by gender. We found that the proportion of females differed by group, and the gap between males and females also varied by group. Overall, males enrolled in STEM at a higher proportion than females and did so regardless of the strength of their academic preparation. Our results provide a novel yet feasible approach to examining gender differences in STEM enrollment in postsecondary education

The structure of Herpesvirus Fusion Glycoprotein B-Bilayer Complex reveals the protein-membrane and lateral protein-protein interaction

Glycoprotein B (gB) is a key component of the complex herpesvirus fusion machinery. We studied membrane interaction of two gB ectodomain forms and present an electron cryotomography structure of the gB-bilayer complex. The two forms differed in presence or absence of the membrane proximal region (MPR) but showed an overall similar trimeric shape. The presence of the MPR impeded interaction with liposomes. In contrast, the MPR-lacking form interacted efficiently with liposomes. Lateral interaction resulted in coat formation on the membranes. The structure revealed that interaction of gB with membranes was mediated by the fusion loops and limited to the outer membrane leaflet. The observed intrinsic propensity of gB to cluster on membranes indicates an additional role of gB in driving the fusion process forward beyond the transient fusion pore opening and subsequently leading to fusion pore expansion

Proteasome activity contributes to prosurvival response upon mild mitochondrial stress in Caenorhabditis elegans

Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the “mitochondrial unfolded protein response” [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the “unfolded protein response activated by mistargeting of proteins” [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity

Investigations on the functions ot "ten-1" during embryonic development in "Caenorhabditis" elegans

Teneurins are a family of phylogenetically conserved proteins. Their most prominent site of expression is the nervous system. Investigations on the expression pattern in vertebrates and invertebrates also revealed the importance for teneurins at sites of morphogenesis during embryonic development. Nevertheless, the function of teneurins remains to be discovered. Teneurins are type II transmembrane proteins. The mechanism of action of teneurins involves the translocation of the intracellular domain into the nucleus. It is postulated that the release of the intracellular domain requires several proteolytic events in the extracellular part, the transmembrane domain and at the cytosolic part. The stimulus of these events is unclear, but there is evidence for homophilic interactions between the teneurins. The advantage of C. elegans as a model organism to investigate the function and mechanism of action of teneurins is that the C. elegans genome codes only for a single ortholog of the vertebrate teneurins. Two different promoters give rise to at least two different transcript versions. The promoters show distinct patterns of activity in the mesoderm and in the ectoderm of the worm. Two independent deletion mutants are characterized as null mutations. Knock-down by RNAi and analysis of the null mutants revealed that ten-1 is essential for embryonic development but also for postembryonic events like larval development and reproduction. Interestingly, investigations on potential genetic interaction partners of ten-1 uncovered functional redundancy between ten-1 and basement membrane associated genes coding for homologs of integrin, dystroglycan, laminin, nidogen and perlecan. Co-staining of chicken teneurin and laminin in some tissues during embryonic development might point to an evolutionary conserved function of teneurins associated with the basement membrane. In this study I used a genome wide approach to obtain a comprehensive list of potential genetic interaction partners of ten-1. I characterized the interaction with phy-1 in more detail. phy-1 is conserved among the phyla and codes for the catalytical domain of the collagen-modifying enzyme prolyl 4-hydroxylase. I found that loss of phy-1 in the ten-1 null mutant background enhances embryonic lethality significantly. Worms die during late elongation because of loss of connectivity between muscles, epidermis and the separating basement membrane. In addition, I present evidence that the function of PHY-1 modifying basement membrane collagen IV is conserved also in C. elegans