RESUMEN
The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Trastorno del Espectro Autista/genética , Citosol/metabolismo , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Quinasas DyrKRESUMEN
Clones of tomato golden mosaic virus (TGMV), a key model for geminivirus research, have been transmitted back to their original host tomato for the first time. In contrast to the high pathogenicity in other solanaceous species, TGMV induced only very mild symptoms: a few chlorotic spots on the leaf lamina for the common variant (formerly strain cs), and limited vein yellowing for the yellow vein variant (yv). Symptoms disappeared over time, though viral DNA remained detectable in newly developed leaves. Both TGMV variants invaded phloem and, occasionally, also mesophyll parenchyma cells in tomato. Complete direct sequencing of rolling circle amplification products of the viral progeny in tomato plants revealed the consensus of the DNA populations for the two genome components (DNA-A, DNA-B) of both TGMV variants. The DNA-A components showed 98.5% and 99.9% nucleotide sequence identity, respectively, with the independently cloned TGMV molecule sequenced initially in 1984, confirming the classification of csTGMV and yvTGMV as variants. The results are discussed with reference to the history of the Brazilian "mosaico dourado" disease in tomato, and the odyssey of TGMV passaging through Nicotiana benthamiana plants and bacteria of numerous laboratories worldwide.