RESUMEN
Macroautophagy/autophagy is a cellular degradation and recycling process that maintains the homeostasis of organisms. A growing number of studies have reported that autophagy participates in infection by a variety of viruses. Porcine reproductive and respiratory syndrome virus (PRRSV) causes severe financial losses to the global swine industry. Although much research has shown that PRRSV triggers autophagy for its own benefits, the exact molecular mechanisms involved in PRRSV-triggered autophagy remain to be fully elucidated. In the current study, we demonstrated that PRRSV infection significantly induced Golgi apparatus (GA) fragmentation, which promoted autophagy to facilitate viral self-replication. Mechanistically, PRRSV nonstructural protein 2 was identified to interact with and degrade the Golgi reassembly and stacking protein 65 dependent on its papain-like cysteine protease 2 activity, resulting in GA fragmentation. Upon GA fragmentation, GA-resident Ras-like protein in brain 2 was disassociated from Golgi matrix protein 130 and subsequently bound to unc-51 like autophagy activating kinase 1 (ULK1), which enhanced phosphorylation of ULK1 and promoted autophagy. Taken together, all these results expand the knowledge of PRRSV-triggered autophagy as well as PRRSV pathogenesis to support novel potential avenues for prevention and control of the virus. More importantly, these results provide the detailed mechanism of GA fragmentation-mediated autophagy, deepening the understanding of autophagic processes.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) infection results in a serious swine disease affecting pig farming worldwide. Despite that numerous studies have shown that PRRSV triggers autophagy for its self-replication, how PRRSV induces autophagy is incompletely understood. Here, we identify that PRRSV Nsp2 degrades GRASP65 to induce GA fragmentation, which dissociates RAB2 from GM130 and activates RAB2-ULK1-mediated autophagy to enhance viral replication. This work expands our understanding of PRRSV-induced autophagy and PRRSV replication, which is beneficial for anti-viral drug development.
Asunto(s)
Autofagia , Aparato de Golgi , Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Animales , Línea Celular , Aparato de Golgi/patología , Síndrome Respiratorio y de la Reproducción Porcina/patología , Síndrome Respiratorio y de la Reproducción Porcina/virología , Porcinos , Replicación ViralRESUMEN
The Golgi complex is a highly dynamic and tightly regulated cellular organelle with essential roles in the processing as well as the sorting of proteins and lipids. Its structure undergoes rapid disassembly and reassembly during normal physiological processes, including cell division, migration, polarization, differentiation, and cell death. Golgi dispersal or fragmentation also occurs in pathological conditions, such as neurodegenerative diseases, infectious diseases, congenital disorders of glycosylation diseases, and cancer. In this review, current knowledge about both structural organization and morphological alterations in the Golgi in physiological and pathological conditions is summarized together with the methodologies that help to reveal its structure.
Asunto(s)
Aparato de Golgi , Enfermedades Neurodegenerativas , Humanos , Aparato de Golgi/metabolismo , Aparato de Golgi/patología , División Celular , Transporte de Proteínas , Enfermedades Neurodegenerativas/metabolismoRESUMEN
The neurons of the lateral spinal nucleus in the spinal cord of young adult rats were studied in transverse and longitudinal planes using the Golgi-Kopsch method and electron microscope. The perikarya were mainly polygonal or spindle shaped, and measured 20 to 35 pm in the longest diameter. They formed a dense column in the dorsolateral funiculus underneath the pial surface. The dendrites followed three patterns. Several of them turned laterally and approached the surface of the spinal cord. Another group of dendrites ran longitudinally within the column of the perikarya. A third group of dendrites turned medially or ventromedially and coursed towards the reticulated portion of the gray matter. Medium-sized neurons located at the margin of this latter portion of the spinal cord sent some of their straight dendrites into the dorsolateral funiculus. Thus, the dendrites of these two populations of neurons appeared as rungs of a ladder in longitudinally-cut spinal cord specimens. Only the initial portions of the axons of the LSN neurons could be impregnated. They originated with a regular axon hillock from either the perikaryon or from one of the primary dendrites and became unimpregnated after a 20 to 40 ?m long course, indicating their myelinated character. Preliminary ultrastructural observations revealed that the laterally directed dendrites of the neurons in the lateral spinal nucleus approached the free surface of the spinal cord and ended immediately underneath the pia mater. Large numbers of fine, unmyelinated fibers were found in the dorsolateral funiculus coursing perpendicular to the laterally and medially oriented dendrites (AU)
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