Biology subjects

Zuniga, J.

Publications and source records attributed to Zuniga, J..

3 recordsLinked to original sources

bioRxiv2025

NAD+ Sensing by PARP7 Regulates the C/EBPβ-Dependent Transcription Program in Adipose Tissue In Vivo

We have identified PARP7, an NAD+-dependent mono(ADP-ribosyl) transferase, as a key regulator of the C/EBP{beta}-dependent proadipogenic transcription program. Moreover, PARP7 is required for efficient adipogenesis and downstream biological functions, including involution of the lactating mammary gland. PARP7 serves as a coregulator of C/EBP{beta}, and depletion of PARP7 causes a dramatic reduction in C/EBP{beta} binding across the genome. PARP7 functions as a sensor of nuclear NAD+ levels to control gene expression. At the relatively high nuclear NAD+ concentrations in undifferentiated preadipocytes, PARP7 is catalytically active for auto- mono(ADP-ribosyl)ation (autoMARylation). As nuclear NAD+ concentrations decline post- differentiation, autoMARylation decreases dramatically. AutoMARylation promotes instability of PARP7 through an E3 ligase-ubiquitin-proteasome pathway mediated by the ADP-ribose (ADPR)-binding ubiquitin E3 ligases DTX2 and RNF114. Genetic depletion of PARP7 in mice promotes a dramatic reduction in a wide array of lipids in the mammary gland fat pads and milk from lactating females, as well as a significant decrease in nicotinamide mononucleotide (NMN), a key nutrient in mothers milk. The latter is due to reduced expression of Nampt, the gene encoding NAMPT, the enzyme that produces NMN, which is a direct transcriptional target of PARP7 and C/EBP{beta}. Collectively, our results extend the biology of PARP7 to adipogenesis and perinatal health. Moreover, our results describe the molecular events that regulate these downstream biological functions.

cell biology↗

bioRxiv2024

Mast cells promote pathology and susceptibility in tuberculosis

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), infects approximately one-fourth of the worlds population. We reported an increased accumulation of mast cells (MCs) in the lungs of macaques with active pulmonary TB (PTB), compared with those with latent TB infection (LTBI). MCs respond in vitro to Mtb exposure via degranulation and by inducing proinflammatory cytokines. In the current study, we demonstrate an increased production of chymase by MCs in granulomas of humans and macaques with PTB. Single-cell (sc) RNA sequencing analysis revealed distinct MC transcriptional programs between LTBI and PTB, with PTB associated MCs enriched in interferon gamma, oxidative phosphorylation, and MYC signaling. In a mouse model, MC deficiency led to improved control of Mtb infection that coincided with reduced accumulation of lung myeloid cells and diminished lung inflammation at chronic stages of infection. Airway transfer of MCs into wild-type Mtb infected mice showed increased neutrophils, decreased recruited macrophages, and elevated Mtb dissemination to the spleen. Together, these findings highlight MCs as active drivers of TB pathogenesis and potential targets for host-directed therapies for TB.

immunology↗

bioRxiv2020

IFN signaling and neutrophil degranulation transcriptional signatures are induced during SARS-CoV-2 infection

The novel virus SARS-CoV-2 has infected more than 14 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Limited information on the underlying immune mechanisms that drive disease or protection during COVID-19 severely hamper development of therapeutics and vaccines. Thus, the establishment of relevant animal models that mimic the pathobiology of the disease is urgent. Rhesus macaques infected with SARS-CoV-2 exhibit disease pathobiology similar to human COVID-19, thus serving as a relevant animal model. In the current study, we have characterized the transcriptional signatures induced in the lungs of juvenile and old rhesus macaques following SARS-CoV-2 infection. We show that genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. We demonstrate that Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. In contrast, pathways involving VEGF are downregulated in lungs of old infected macaques. Using samples from humans with SARS-CoV-2 infection and COVID-19, we validate a subset of our findings. Finally, neutrophil degranulation, innate immune system and IFN gamma signaling pathways are upregulated in both tuberculosis and COVID-19, two pulmonary diseases where neutrophils are associated with increased severity. Together, our transcriptomic studies have delineated disease pathways to improve our understanding of the immunopathogenesis of COVID-19 to facilitate the design of new therapeutics for COVID-19.

immunology↗