Ablation of arginyl‐tRNA‐protein transferase in oligodendrocytes impairs central nervous system myelination

Abstract

Addition of arginine (Arg) from tRNA can cause major alterations of structure and function of protein substrates. This post-translational modification, termed protein arginylation, is mediated by the enzyme arginyl-tRNA-protein transferase 1 (Ate1).Arginylation plays essential roles in a variety of cellular processes, including cell migration, apoptosis, and cytoskeletal organization. Ate1 is associated with neuronal functions such as neurogenesis and neurite growth. However, the role of Ate1 in glial development, including oligodendrocyte (OL) differentiation and myelination processes in the central nervous system, is poorly understood. The present study revealed a peak in Ate1 protein expression during myelination process in primary cultured OLs. Post-transcriptional downregulation of Ate1 reduced the number of OL processes, and branching complexity, in vitro. We conditionally ablated Ate1 from OLs in mice using 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase-Cre promoter ("Ate1-KO" mice), to assess the role of Ate1 in OL function and axonal myelination in vivo. Immunostaining for OL differentiation markers revealed a notable reduction of mature OLs in corpus callosum of 14-day-old Ate1-KO, but no changes in spinal cord, in comparison with wild-type controls. Local proliferation of OL precursor cells was elevated in corpus callosum of 21-day-old Ate1-KO, but was unchanged in spinal cord. Five-month-old Ate1-KO displayed reductions of mature OL number and myelin thickness, with alterations of motor behaviors. Our findings, taken together, demonstrate that Ate1 helps maintain proper OL differentiation and myelination in corpus callosum in vivo, and that protein arginylation plays an essential role in developmental myelination.

Arginyltransferase 1 modulates p62-driven autophagy via mTORC1/AMPk signaling

“…Genetic experiments conducted in several tissues highlight the importance of Ate1 in mTOR-related metabolic processes, such as, cell migration, proliferation, and differentiation [ 11 , 16 , 68 , 69 ]. In this regard, we recently demonstrated that silencing Ate1 in primary oligodendrocyte cultures reduces the extent and complexity of processes during differentiation and myelination [ 19 ]. In vivo , Ate1 conditional KO in mouse oligodendrocytes leads to uncompacted myelin layers in spinal cord axons, a process regulated by the Akt/mTOR signaling in the central nervous system [ 70 , 71 ].…”

“…Ate1 mediates posttranslational arginylation of a large family of proteins, including signaling and regulatory proteins, cytoskeletal components, transcription factors, endoplasmic reticulum (ER)-residing and secretory proteins, thereby affecting diverse cell biological processes and normal physiology [ 7 – 16 ]. Indeed, constitutive deletion of mouse Ate1 is embryonic-lethal due to defective heart development [ 17 ], whereas postnatal Ate1 ablation produces broad phenotypes, including neurological and metabolic abnormalities [ 18 , 19 ].…”

Decreased RNA polymerase III subunit expression leads to defects in oligodendrocyte development

“…Moreover, tRNA availability for protein arginylation is an additional way tRNAs may be important for OL maturation and myelination. The transfer of arginine from tRNA onto proteins, or arginylation, is a post-translational modification catalyzed by arginyl-protein-transferase 1 (Ate1) and has recently been shown to play a critical role in OL maturation ( Palandri et al, 2022 ). Various cytoskeletal regulators of OL maturation are subject to arginylation and in primary cultures of mouse OLs with a genetic ablation in Ate1, branching complexity was significantly reduced while in vivo, these mice showed fewer mature (MOG+ or MBP+) OLs, which the authors suggested could be due to impaired OL differentiation ( Palandri et al, 2022 ).…”

“…The transfer of arginine from tRNA onto proteins, or arginylation, is a post-translational modification catalyzed by arginyl-protein-transferase 1 (Ate1) and has recently been shown to play a critical role in OL maturation ( Palandri et al, 2022 ). Various cytoskeletal regulators of OL maturation are subject to arginylation and in primary cultures of mouse OLs with a genetic ablation in Ate1, branching complexity was significantly reduced while in vivo, these mice showed fewer mature (MOG+ or MBP+) OLs, which the authors suggested could be due to impaired OL differentiation ( Palandri et al, 2022 ). It is interesting to note that biallelic variants of the cytoplasmic arginine aminoacyl-tRNA synthetase ( RARS1 ) are associated with a hypomyelinating leukodystrophy ( Nafisinia et al, 2017 ).…”