2. Academic Validation
  3. Environmental Amino Acid Sensing Regulates the Rate of ASC Translation and NLRP3 Inflammasome Assembly

Environmental Amino Acid Sensing Regulates the Rate of ASC Translation and NLRP3 Inflammasome Assembly

  • bioRxiv. 2026 Jan 20:2026.01.16.699988. doi: 10.64898/2026.01.16.699988.
Mikel D Haggadone 1,  Brian P Goldspiel 2 3,  Aoife O'Farrell 4,  Nora T Kiledjian 5,  Montana Knight 2 6,  Talia R Smith 1,  Elena Anderson 7,  Víctor R Vázquez Marrero 1,  Mark A Boyer 1,  Peining Jimmy Xu 8,  Michael Scaglione 2,  Zachary M Powers 9,  Clemence Queriault 2,  Aaron Wu 2,  Qihua Yang 10,  Mary X O'Riordan 9,  Arjun Raj 4 11,  Clementina Mesaros 8,  Crystal S Conn 5,  Sunny Shin 1,  Will Bailis 2 12
Affiliations

Affiliations

  • 1 Department of Microbiology, Penn Center for Genome Integrity, Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 3 Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 7 School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 10 Cancer Biology Program, Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 11 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 12 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
PMID: 41648523 DOI: 10.64898/2026.01.16.699988
Abstract

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein signaling complex that triggers pyroptotic cell death and interleukin (IL)-1 family cytokine release during Infection and cell injury. Its assembly is driven by the adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC), whose filamentation forms a supramolecular speck upon NLRP3 activation to amplify inflammasome signaling. While the NLRP3 inflammasome is well appreciated as a sensor of environmental danger and damage, little is known about how homeostatic environmental factors like dietary metabolites regulate its activity. Here, we find that environmental availability of the branched-chain Amino acids (BCAAs), leucine, isoleucine, and valine, controls NLRP3 inflammasome assembly. While ASC is typically viewed as a constitutively expressed, unregulated inflammasome component, we find that Toll-like Receptor 4 (TLR4) activation triggers localization of ASC mRNA to the perinuclear space. Moreover, our data demonstrate that ASC undergoes TLR4-driven translational bursting from polyribosomes during inflammasome priming. This translational engagement is dependent on BCAA availability and mechanistic target of rapamycin (mTOR) activity, which regulate the kinetics of inflammasome assembly. In contrast, the translation of NLRP3 and Caspase-1 is largely insensitive to these inputs. Furthermore, we find that BCAAs regulate NLRP3 inflammasome activation in both mouse and human macrophages, in the context of Bacterial infection, and during lipopolysaccharide (LPS)-induced sepsis in vivo. Altogether, this work unveils a novel inflammasome priming event governed by the amino acid environment. These findings further highlight how the activity of proteins maintained in equilibrium like ASC can be dynamically regulated through rapid changes in mRNA translation.

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