Escoll Guerrero, P. | bioRxiv Science

bioRxiv2023

MYC and MAX drive the reactivation of the genome after mitosis

Shortly after cell division, a robust wave of hyper-transcription reactivates the genome1-3. This phenomenon is particularly pronounced in pluripotent cells4, which necessitate rapid transcrip-tome reactivation to maintain their undifferentiated state and prevent premature differentiation. While recent work has illuminated how specific groups of genes are reactivated4-8, the mechanisms enabling the global, efficient and accurate post-mitotic reactivation of the genome remain unknown. Here we elucidate the direct involvement of the MYC/MAX transcription factors in the post-mitotic reactivation of pluripotent mouse embryonic stem cells. While MYC undergoes extensive phosphorylation and largely dissociates from its DNA binding sites during mitosis, we report that MAX remains bound to its targets, preferentially at promoters, and facilitates early recruitment of MYC following mitosis. Through the application of MYC/MAX heterodimerization inhibitors, we demonstrate their indispensable role in sustaining hyper-transcription in ES cells, including during the critical transition from mitosis to G1 phase. Our findings uncover a novel role for MAX in mitotic book-marking, highlighting its pivotal role in post-mitotic MYC recruitment and the re-establishment of high global transcription levels. These findings hold significant implications for medically relevant contexts, particularly when cell proliferation is of paramount importance9. We anticipate that the study of mitotic bookmarking by MYC and MAX and of the effects of anticancer drugs targeting MYC/MAX interactions in such process10-12 will be relevant for our understanding of cancer and its potential treatments.

molecular biology↗

bioRxiv2022

Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages

Leptospira interrogans are pathogenic bacteria responsible for leptospirosis, a worldwide zoonosis. All vertebrates can be infected, and some species like humans are susceptible to the disease whereas rodents such as mice are resistant and become asymptomatic renal carriers. Leptospires are stealth bacteria that are known to escape several immune recognition pathways and resist killing mechanisms. We recently published that leptospires may survive intracellularly and exit macrophages, in part by escaping xenophagy, a pathogen-targeting form of autophagy. Interestingly, autophagy is one of the antimicrobial mechanisms often highjacked by bacteria to evade the host immune response. In this study we therefore explored whether leptospires subvert the key molecular players of autophagy to facilitate the infection. We showed in macrophages that leptospires triggered a specific accumulation of autophagy-adaptor p62 in puncta-like structures, without major alteration of autophagy flux. Unlike active bacterial mechanisms described to date, we demonstrated that leptospires trigger p62 accumulation using a passive mechanism of LPS signaling via TLR4/TLR2. p62 is a central pleiotropic protein, not only involved in autophagy, but also mediating cell stress and death, via the translocation of transcription factors. We demonstrated that Leptospira-driven accumulation of p62 induced the translocation of transcription factor NRF2. However, NRF2 translocation upon Leptospira infection did not result as expected in antioxydant response, but dampened the production of inflammatory mediators such as iNOS/NO, TNF and IL6. Overall, these findings highlight a novel passive bacterial mechanism linked to p62/NRF2 signaling that decreases inflammation and contributes to the stealthiness of leptospires.

immunology↗