Biology subjects

Hulahan, J.

Publications and source records attributed to Hulahan, J..

3 recordsLinked to original sources

bioRxiv2026

HDAC5-encoded Microprotein NISM Mediates Nucleolar Formation and Ribosomal RNA Synthesis

Ribosome biogenesis is the process by which ribosomal RNA (rRNA) and ribosomal proteins are synthesized, processed, and assembled into functional ribosomes. This process begins in the nucleolus, a multiphase liquid condensate. Here, we discover an arginine-rich disordered nucleolar microprotein encoded within the HDAC5 5'-UTR that we termed Nucleolar Integrity and Stress Microprotein (NISM). NISM overexpression leads to impaired rDNA transcription, triggering nucleolar stress, p53 activation, and suppressed proliferation. NISM knockout causes disruption of nucleolar structure and also induces p53 activation. Mechanistically, NISM interacts with the DExH-box RNA helicase DHX9 and regulates its activities related to pre-rRNA synthesis. Computational analyses and polymer physics-based mathematical modeling revealed that NISM coordinates nucleolar formation and pre-rRNA synthesis by enhancing the liquid-liquid phase separation of DHX9. This study establishes NISM as a regulator of nucleolar biology and deepens our understanding of how disordered microproteins can facilitate the formation of membraneless organelles.

molecular biology↗

bioRxiv2025

Effect of obesity on the acute response to SARS-CoV-2 infection and development of post-acute sequelae of COVID-19 (PASC) in nonhuman primates

Long-term adverse consequences of SARS-CoV-2 infection, termed "long COVID" or post-acute sequelae of COVID (PASC), are a major component of overall COVID-19 disease burden. Prior obesity and metabolic disease increase the severity of acute disease, but SARS-CoV-2 infection also contributes to the development of new-onset metabolic disease. Since the COVID pandemic occurred in the context of the global obesity epidemic, an important question is the extent to which pre-existing obesity modifies long-term responses to SARS-CoV-2 infection. We utilized a nonhuman primate model to compare the effects of infection with the SARS-CoV-2 delta variant in lean and obese/insulin-resistant adult male rhesus macaques over a 6-month time course. While some longitudinal responses to SARS-CoV-2 infection, including overall viral dynamics, SARS-CoV-2-specific IgG induction, cytokine profiles, and tissue persistence of viral RNA, did not appreciably differ between lean and obese animals, other responses, including neutralizing Ab dynamics, lung pathology, body weight, degree of insulin sensitivity, adipocytokine profiles, body temperature, and nighttime activity levels were significantly different in lean versus obese animals. Furthermore, several parameters in lean animals were altered following SARS-CoV-2 infection to resemble those in obese animals. Notably, persistent changes in multiple parameters were present in most animals, suggesting that PASC may be more prevalent than estimated from self-reported symptoms in human studies.

pathology↗

bioRxiv2023

Evolutionary arms race between SARS-CoV-2 and interferon signaling via dynamic interaction with autophagy.

SARS-CoV-2 emerged, and is evolving to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling activated only in bystander cells. This balance of innate activation and viral evasion has important consequences, but the pathways involved are incompletely understood. Here we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons, and thus permissivity to infection. Mechanistically, autophagy genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, upon loss of autophagy increased MAVS overcomes ORF9b-mediated antagonism suppressing infection. This has led to the evolution of SARS-CoV-2 variants to express higher levels of ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of autophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.

microbiology↗