Extracellular Lipopolysaccharide Triggers the Release of Unconjugated Interferon-Stimulated Gene 15 (ISG15) Protein from Macrophages via Type-I Interferon/Caspase-4/Gasdermin-D Pathway.

Sudiksha Pandit, Lindsay Grace Miller, Indira Mohanty, Santanu Bose

Abstract read

In one paragraph

Article in Pathogens (Basel, Switzerland), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

4 authors.

Sudiksha PanditDepartment of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA.ORCID 0000-0002-4994-9810

Lindsay Grace MillerDepartment of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA.

Indira MohantyDepartment of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA.

Santanu BoseDepartment of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA.

Funding

Molecular and cellular mechanism regulating innate immunity and inflammation during pattern recognition receptor activation and respiratory virus infectionR01AI083387 · NIAID · WASHINGTON STATE UNIVERSITY · PI BOSE, SANTANU · 2010 to 2021

$3.1M

NIAID NIH HHS R01 AI083387NIH HHS 1R01AI083387-12

6 · The paper itself

Abstract

Interferon-stimulated gene 15 (ISG15) is an interferon-induced ubiquitin-like protein that plays an important role in antiviral defense and inflammatory responses, primarily through the process of ISGylation, whereby ISG15 is covalently conjugated to target proteins. Beyond its intracellular functions, a portion of free unconjugated ISG15 is also released into the extracellular environment during infections and diseases such as cancer. Extracellular ISG15 is known to regulate immune cell activity and cytokine production. Despite its immune-modulatory role, how ISG15 is released from cells has remained unclear. In this study, we have identified a non-lytic mechanism by which human macrophages release ISG15. Using lipopolysaccharide (LPS) as a stimulus, we show that extracellular LPS triggers unconjugated ISG15 release by utilizing plasma membrane-localized Gasdermin D (GSDMD) pores. Mechanistically, LPS via the autocrine/paracrine action of type-I interferon (IFN) activates caspase-4 (Casp4) to cleave the N-terminal domain of GSDMD for the formation of cell surface GSDMD pores that permit the extracellular release of unconjugated ISG15 in the absence of lytic cell death. Together, our studies have identified the IFN-Casp4-GSDMD axis as a previously unrecognized non-classical pathway for unconjugated ISG15 release from cells.

Indexed as

Caspases, InitiatorCytokinesInterferon Type IIntracellular Signaling Peptides and ProteinsLipopolysaccharidesMacrophagesPhosphate-Binding ProteinsSignal TransductionUbiquitinsGasderminsHumansCASP4 protein, humanCaspases, InitiatorCytokinesGasderminsGSDMD protein, humanInterferon Type IIntracellular Signaling Peptides and ProteinsISG15 protein, humanLipopolysaccharidesPhosphate-Binding ProteinsUbiquitinscaspase-4Gasdermin Dhuman macrophagesInterferon-stimulated gene 15lipopolysaccharidetype-I interferon

Identifiers

PMID41599106

DOI10.3390/pathogens15010122

PMCPMC12844758

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.