Couturier, A. | Search bioRxiv

bioRxiv2022

Protective role of podocytic IL-15/STAT5 pathway in experimental focal and segmental glomerulosclerosis

During glomerular diseases, podocyte-specific pathways can modulate the intensity of the lesions and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of chronic kidney diseases. The Janus Kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently described in intrinsic kidney cells. Here, we show, for the first time, that STAT5 is activated in human podocytes in focal segmental glomerulosclerosis (FSGS). Additionally, Stat5 podocyte-specific inactivation aggravates the functional and structural alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of the autophagic flux. Finally, Interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes and its administration alleviates glomerular injury in vivo by maintaining the autophagy flux in podocytes. In conclusion, activating podocytic STAT5 with commercially available IL-15 represents a new therapeutic avenue with the potential for FSGS.

pathology↗

bioRxiv2022

Real-time visualisation of conjugation reveals the molecular strategy evolved by the conjugative F plasmid to ensure the sequential production of plasmid factors during establishment in the new host cell

DNA conjugation is a contact-dependent horizontal gene transfer mechanism responsible for disseminating drug resistance among bacterial species. Conjugation remains poorly characterised at the cellular scale, particularly regarding the reactions occurring after the plasmid enters the new host cell. Here, we use live-cell microscopy to visualise the intracellular dynamics of conjugation in real time. We reveal that the transfer of the plasmid in single-stranded DNA (ssDNA) form followed by its conversion into double-stranded DNA (dsDNA) are fast and efficient processes that occur with specific timing and subcellular localisation. Notably, the ss-to-dsDNA conversion is the critical step that governs the timing of plasmid-encoded protein production. The leading region that first enters the recipient cell carries single-stranded promoters that allow the early and transient synthesis of leading proteins immediately upon entry of the ssDNA plasmid. The subsequent ss-to-dsDNA conversion turns off leading gene expression and licences the expression of the other plasmid genes under the control of conventional double-stranded promoters. This elegant molecular strategy evolved by the conjugative plasmid allows for the timely production of factors sequentially involved in establishing, maintaining and disseminating the plasmid.

microbiology↗