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The Rab32-LRMDA-Retriever Complex is a Key Regulator of Intestinal Immune Homeostasis.

Ran Song1, Chigozie Ngoka1,2, Amika Singla1

  • 1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA.

Biorxiv : the Preprint Server for Biology
|August 12, 2025
PubMed
Summary
This summary is machine-generated.

Leucine-rich melanocyte differentiation-associated protein (LRMDA) is crucial for intestinal immune homeostasis. LRMDA, working with Rab32 and Retriever, regulates endolysosomal trafficking in innate immune cells, preventing inflammation and infection.

Keywords:
Dextran sodium sulfate (DSS)LRMDALysosome related organelle (LRO)N-ethyl-N-nitrosourea (ENU)Rab32Retrieverinflammatory bowel disease (IBD)innate immunityvesicle trafficking

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Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • Intestinal homeostasis depends on immune cells, the epithelium, and the microbiome.
  • Innate immune cells must process gut microbes to protect against injury and infection.
  • The endolysosomal system is vital for clearing microbes and initiating inflammatory responses.

Purpose of the Study:

  • To identify key regulators of intestinal immune homeostasis.
  • To understand how innate immune cells sense and respond to gut microbes.
  • To elucidate the role of LRMDA in intestinal immunity.

Main Methods:

  • Forward genetic screening in ENU-mutagenized mice.
  • CRISPR/Cas9 validation of identified genes.
  • Hematopoietic chimera and conditional knockout mouse models.
  • Proteomic, cellular, and biochemical analyses.

Main Results:

  • LRMDA was identified as a key regulator of intestinal homeostasis.
  • LRMDA functions in CD11c+ innate immune cells like dendritic cells and macrophages.
  • LRMDA forms a complex with Rab32 and Retriever, regulating endolysosomal trafficking.
  • Loss of LRMDA or Retriever increases susceptibility to colitis and Listeria infection.

Conclusions:

  • The Rab32-LRMDA-Retriever complex is essential for endolysosomal trafficking in innate immune cells.
  • This complex plays a critical role in maintaining intestinal immune homeostasis.
  • Disruptions in this pathway can lead to inflammatory disorders and increased infection susceptibility.