Biology subjects

Cabrini, M.

Publications and source records attributed to Cabrini, M..

5 recordsLinked to original sources

bioRxiv2026

A dsRNA Virus Converts Early Endosomes into Stable Replication Organelles Through Maturation Arrest and Retrograde Transport

Infectious bursal disease virus (IBDV) and infectious pancreatic necrosis virus (IPNV) are major animal pathogens that impose a heavy burden on the poultry and aquaculture industries. Yet, major aspects of their unique replication program remain unknown. IBDV is unusual among double-stranded RNA viruses in that it replicates in association with host endosomes. We previously demonstrated this association to be orchestrated by the viral protein VP3 and the early endosomal lipid phosphatidylinositol 3-phosphate [PtdIns(3)P], suggesting an essential role for VP3 in forming birnaviruses specialized replication compartments. Here, combining high-resolution fluorescence and correlative light-electron microscopy with diverse molecular and biochemical analyses, we define how the IBDV protein VP3 targets and remodels host endosomes, and establish that endosome-associated replication is conserved in members of the Birnaviridae family. We show that IBDV VP3 targets early endosomes via the PtdIns(3)P effector Early Endosomal Antigen 1 (EEA1) to arrest their maturation and prompt their association with the Golgi complex via ESCPE-1-mediated retrograde transport. We further show that IPNV also exploits endosomal membranes for replication in a PtdIns(3)P dependent manner, although for this virus VP3 engages endosomes through an EEA1-independent mechanism yet to be determined. This work uncovers how birnaviruses exploit a single viral protein to orchestrate endosome remodeling and intracellular trafficking to establish specialized replication compartments while revealing both conserved and host-adapted features of birnaviruses replication.

cell biology↗

bioRxiv2026

3' Plasma Membrane Phosphoinositides Sustain ROS Production at Persistent Non-canonical Phagocytic Cups that Promote Macrophage Control of Aspergillus fumigatus Hyphae

Aspergillus fumigatus is the leading cause of aspergillosis in immunocompromised individuals. Because A. fumigatus hyphae rapidly outgrow macrophages, they are generally thought to evade macrophage-mediated control once they exceed the size limits of phagocytosis, enabling invasive growth within host tissues. Here, we show that macrophages circumvent this limitation by capturing hyphal tips within persistent tubular phagocytic cups. Rather than resolving into complete phagosomes or disengaging from their targets, these long-lived open compartments maintain key features of phagocytic cups while progressively acquiring characteristics of maturing phagosomes. Their persistence sustains localized NOX2-dependent reactive oxygen species production, leading to hyphal-tip damage and restriction of fungal growth. Sustained PI(3,4)P2 signaling downstream of class I PI3K promotes prolonged NOX2 activity and is required for efficient hyphal restriction. Together, our findings reveal a previously unrecognized antifungal mechanism in which persistent phagocytic cups transform incomplete phagocytosis into sustained antimicrobial activity, extending macrophage control beyond the physical limits of engulfment.

cell biology↗

bioRxiv2024

DROSHA, DICER and Damage-Induced long ncRNA control BMI1-dependent transcriptional repression at DNA double-strand break

Genome integrity is safeguarded by the DNA damage response (DDR). Controlled transcriptional dampening of genes surrounding DNA double-strand breaks (DSBs) has been shown to facilitate DNA repair. This phenomenon, defined as DSB-induced silencing in cis (DISC), involves the DDR apical kinase ATM and the Polycomb Repressive Complex 1 (PRC1). Conversely, DSBs have also been reported to induce de novo transcription of damaged-induced long non-coding RNAs (dilncRNAs) in a MRE11-RAD50-NBS1 (MNR) complex-dependent manner. MRN also controls the recruitment to DSB of the ribonuclease DROSHA, which together with DICER, stimulates DDR signaling and DNA repair. Here, we reconcile these apparently contrasting observations by showing that dilncRNA, together with DROSHA and DICER, but not GW182-like proteins required for miRNA-mediated gene silencing, controls DISC. Indeed, similarly to ATM, MRN inhibition abolishes DISC while pharmacological enhancement of DICER ribonuclease activity by Enoxacin improves DISC. Importantly, Enoxacin administration restores DISC upon ATM inhibition, demonstrating that DICER promotes DISC independently from ATM. Differently, Enoxacin does not restore DISC upon MRN inhibition, suggesting that DICER acts downstream to dilncRNA biogenesis and DROSHA recruitment. Mechanistically, we show that DROSHA and DICER control the recruitment of the PRC1 component BMI1 at DSBs and the consequent H2A-K119 ubiquitination. Upon DSBs formation, BMI1 and DROSHA interact in an RNA-dependent manner. Indeed, BMI1 associates to dilncRNA and do so in a DROSHA- and DICER-dependent manner. Importantly, inhibition of dilncRNA function by antisense oligonucleotides or Cas13-mediated targeting is sufficient to reduce BMI1 recruitment and DISC at individual loci. We propose that dilncRNAs together with DROSHA and DICER control DISC at genomic DSB by supporting PRC1 recruitment and chromatin ubiquitination.

molecular biology↗

bioRxiv2021

DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is known to be more common in the elderly, who show also more severe symptoms and a higher risk of hospitalization and death. Here we show that the expression of the Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV2 cell receptor, increases during aging in mouse and human lungs, and following telomere shortening or dysfunction in mammalian cells and in mouse models. This increase is regulated at the transcription level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Indeed, ATM inhibition or the selective inhibition of telomeric DDR, through the use of antisense oligonucleotides, prevents Ace2 upregulation following telomere damage, in cultured cells and in mice. We propose that during aging telomeric shortening, by triggering DDR activation, causes the upregulation of ACE2, the SARS-CoV2 cell receptor, thus making the elderly likely more susceptible to the infection.

cell biology↗

bioRxiv2018

DROSHA associates to DNA damage sites and is required for DNA repair

The DNA damage response (DDR) is the signaling cascade through which a cell recognizes DNA lesions, and promotes their resolution via the repair pathways of Non-Homologous End Joining (NHEJ), or Homologous Recombination (HR). We recently demonstrated that DROSHA boosts DDR signaling by processing damage-induced long non-coding RNAs into smaller DNA damage response RNAs (DDRNAs). However, the location at which DROSHA exerts its DDR functions, relative to sites of DNA damage, remains unknown.\n\nTo investigate DROSHAs localization during DDR activation, we used the DiVA cellular system, which allows the controlled induction of several DNA double strand breaks (DSBs) in the human genome. Indeed, by genome wide chromatin immunoprecipitation followed by next generation sequencing, we demonstrate that DROSHA associates with DSBs. In support of this, DSB-recruitment of DROSHA is detectable at the single-cell level by Proximity Ligation Assay between DROSHA and known DDR markers, and by DNA damage in situ ligation followed by Proximity Ligation Assay (DI-PLA), which demonstrates proximity of DROSHA to DNA ends. DROSHA recruitment occurs at both genic and inter-genic DSBs, suggesting that its recruitment is independent from ongoing transcription preceding damage generation. DROSHAs recruitment to DNA lesions occurs throughout the cell cycle, and with a preference for NHEJ-prone DSBs. Consistently, inhibition of the HR pathway increases DROSHA recruitment, and DROSHA knock down strongly impairs NHEJ efficiency in a GFP-reporter cellular system for monitoring NHEJ DNA repair. Overall, these results demonstrate that DROSHA acts locally at sites of DNA damage to promote NHEJ DNA repair.

cell biology↗