Noncanonical Activity of Seryl-tRNA Synthetase Is Involved in Vascular Development

Abstract

Abstract-Vascular endothelial growth factor (Vegf) plays central roles in the establishment of stereotypic vascular patterning in vertebrates. However, it is not fully understood how the network of blood vessels is established and maintained during vascular development. A zebrafish ko095 mutant presented the disorganized vessels with abnormal branching of the established intersegmental vessels (ISVs) after 60 hours postfertilization. The gene responsible for ko095 encodes seryl-tRNA synthetase (Sars) with a nonsense mutation. The abnormal branching of ISVs in ko095 mutant was suppressed by the introduction of either wild-type Sars or a mutant Sars (T429A) lacking the enzymatic activity that catalyzes aminoacylation of transfer RNA for serine (canonical activity), suggesting that the abnormal branching is attributable to the loss of function of Sars besides its canonical activity. We further found the increased expression of vegfa in ko095 mutant at 72 hours postfertilization, which was also reversed by the introduction of Sars (T429A). Furthermore, the abnormal branching of ISVs in the mutant was suppressed by knockdown of vegfa or vegfr2 (kdra and kdrb). Knockdown of vegfc or vegfr3 rescued the abnormal ISV branching in ko095 mutant. These results suggest that the abnormal ISV branching in ko095 mutant is caused by the activated Vegfa-Vegfr2 signal and requires the Vegfc-Vegfr3 signal, because the latter is needed for general angiogenesis. Hence, we conclude that noncanonical activity of Sars is involved in vascular development presumably by modulating the expression of vegfa. 4,5 The network of trunk vessels along somite boundaries is well conserved among vertebrates. Primary angiogenic sprouts emanate bilaterally from the dorsal aorta and forms the intersegmental vessels (ISVs) along the somites from ventral to dorsal and the dorsal longitudinal anastomotic vessels along the head to tail axis at the most dorsal side. The secondary sprouts from the posterior cardinal vein connecting to the primary ISVs becomes the intersegmental veins. The remaining secondary sprouts branch to form the parachordal vessels near the horizontal myoseptum that develops toward the head or tail. 5,6 Angiogenic sprouting is regulated by tip cells and the cells following the tip cells, the stalk cells. 2,3,7 In these 2 types of cells, the importance of vascular endothelial growth factor (Vegf)-mediated regulation has been unraveled. Vegfa induces the migration of the tip cells and the expression of a Notch ligand Dll4 that is exclusively expressed in the endothelial cells, via Vegfr2 in the tip cells. Subsequently, Dll4 represses the expression of Vegfr2 and Vegfr3 via Notch expressed in the stalk cells to inhibit the responses to Vegfs. 2,3,8 Primary ISV sprouts express both Vegfr2 and Vegfr3, suggesting that differential expression of Vegfrs affects the vascular development via modulating the responsiveness of endothelial cells to Vegfs. 7,9 Consistently, deletion of a single Dll4 allele in mice and knockdown of dll4 in zebrafish r...

New Aminoacyl-tRNA Synthetase-like Protein in Insecta with an Essential Mitochondrial Function

“…The N-terminal coiled-coil domain of SRS is unique among ARS, but similar structures are common in other nucleic acid-binding proteins (4). Whether the N-terminal domain of SRS interacts with other nucleic acids is unknown, but it has been reported that SRS plays a role during the development of zebrafish (5)(6)(7). Thus, the coiled-coil domain of SRS may be carrying out functions other than tRNA recognition.…”

Seryl-tRNA Synthetases in Translation and Beyond

“…[40] Two independent forward-genetic studies in zebrafish demonstrated involvement of vertebrate SerRS in vascular development. [41,42] Random chemical mutagenesis introduced premature stop-codons within the gene for cytosolic SerRS, leading to abnormal blood vessel formation and defective blood circulation in the zebrafish embryo. The human SerRS also affects angiogenesis, and SerRS influence on vascular development is independent of its catalytic activity.…”

“…The human SerRS also affects angiogenesis, and SerRS influence on vascular development is independent of its catalytic activity. [41] The noncanonical activity was linked to the dysregulation of vascular endothelial growth factor A (VEGFA) expression, a key regulator of angiogenesis and vasculogenesis. [41] The model of canonical or bacterial-type SerRS (A) and atypical or methanogenic-type SerRS (B) in complex with tRNA.…”

“…[41] The noncanonical activity was linked to the dysregulation of vascular endothelial growth factor A (VEGFA) expression, a key regulator of angiogenesis and vasculogenesis. [41] The model of canonical or bacterial-type SerRS (A) and atypical or methanogenic-type SerRS (B) in complex with tRNA. Bacterialtype SerRS complex with tRNA is modelled according to the published structure of Thermus thermophilus SerRS complex.…”

tRN-A-RS Acts As Biomarker for Cancer and Other Diseases

“…Immune cells inflict tumor initiation, growth and progression intervened by proinflammatory cytokines. IARS, HARS and AARS are efficiently cleaved by granzyme B, a serine protease released by cytoplasmic granules within cytotoxic T cells and natural killer, NK, cells and involved in the induction of programmed cell death in the target cell, thus eliminating cells that have become cancerous, to generate autoantigenic fragments with chemokine activity [115]. QARS, known to be an apoptosis suppressor, inhibits the pro-apoptotic signaling pathway through glutamine-dependent interaction with apoptosis signal-regulating kinase 1, ASK1, induced by heat shock, irradiation, and c-Myc overexpression.…”