Commensal bacteria direct selective cargo sorting to promote symbiosis
Abstract
Mucosal immunity protects a host from intestinal inflammation and infection and is profoundly influenced by symbiotic bacteria. Here we report that in mice symbiotic bacteria directed selective cargo sorting in Paneth cells to promote symbiosis through Nod2, a cytosolic bacterial sensor, and the multifunctional protein kinase LRRK2, both encoded by inflammatory bowel disease (IBD)-associated genes. Commensals recruited Nod2 onto lysozyme-containing dense core vesicles (DCVs), which was required for DCV localization of LRRK2 and a small GTPase, Rab2a. Deficiency of Nod2, LRRK2 or Rab2a or depletion of commensals resulted in lysosomal degradation of lysozyme. Thus, commensal bacteria and host factors orchestrate the lysozyme-sorting process to protect the host from enteric infection, implicating Paneth cell dysfunction in IBD pathogenesis.
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The use of siRNA technology in 3D organoid cultures has been very limited.
“The use of siRNA technology in 3D organoid cultures has been very limited [48,49,50], likely also due to the technical challenge of delivering siRNAs through the extracellular matrix to organoids in situ [49].”
From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [50]
Nod1 and Nod2 play a key role in mediating microbe-host cross talk, including lymphoid tissue genesis, Paneth cell function, neutrophil priming, hematopoiesis, and 5-HT signaling.
“Nucleotide-binding oligomerization domain 1 (Nod1), together with Nod2, as classic pattern recognition receptors, play a key role in mediating the microbe-host cross talk, including lymphoid tissue genesis (Bouskra et al., 2008), Paneth cell function in the intestine (Zhang et al., 2015), neutrophil priming (Clarke et al., 2010), hematopoiesis (Iwamura et al., 2017), and 5-hydroxytryptamine (5-HT)”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Zhang et al., 2015
Rab2a regulates cargo sorting events in neurons in C. elegans and intestinal Paneth cells.
“Studies have shown that Rab2a regulates cargo sorting events in neurons in C. elegans and intestinal Paneth cells (Edwards et al., 2009; Sumakovic et al., 2009; Zhang et al., 2015).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Zhang et al., 2015
In cultured intestinal organoids, Rab2a knockdown leads to lysozyme being targeted for degradation in lysosomes instead of being stored in dense-core granules in Paneth cells.
“In cultured intestinal organoids, Rab2a knockdown led to lysozyme being targeted for degradation in lysosomes instead of being stored in DCGs in Paneth cells (Zhang et al., 2015).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Zhang et al., 2015
Rab10 colocalizes with Chga on dense-core granules in wild-type chromaffin cells.
“Rab10 colocalized with Chga on DCGs in WT chromaffin cells (Figure S3O), consistent with the previous publication indicating Rab10 localization on DCGs in intestinal Paneth cell (Zhang et al., 2015).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Zhang et al., 2015
Previous study found highly restricted expression of Nod1 in pancreatic beta cells but not in other pancreatic cells.
“Interestingly, our previous study found a highly restricted expression of Nod1 in pancreatic beta cells but not in other pancreatic cells (Zhang et al., 2015).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Zhang et al., 2015
Knockdown of Rab2a led to lysosomal degradation of lysozyme in intestinal Paneth cells.
“Knockdown of Rab2a led to lysosomal degradation of lysozyme in intestinal Paneth cells (Zhang et al., 2015).”
From Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells (2021) · cites this paper as Zhang et al., 2015
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References 54 · Cited by 206
- Authors
- Zhang, Q., Pan, Y., Yan, R., Zeng, B., Wang, H., Zhang, X., Li, W., Wei, H., & Liu, Z.
- Affiliations
- Chinese Academy of Sciences (CN)
- Army Medical University (CN)
- Corresponding author
- Wei, Hong
- Liu, Zhihua
- Venue
- Nature Immunology
- Published
- 2015-08-03
- Volume
- 16
- Issue
- 9
- Pages
- 918-926
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W1656401266
- Cited by
- 206
- References
- 54
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 13 · 2023: 22 · 2022: 13 · 2021: 19 · 2020: 26 · 2019: 23 · 2018: 25 · 2017: 26 · 2016: 14 · 2015: 3
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- commensal bacteria, Paneth cells, NOD2, LRRK2, RAB2A, lysozyme, dense core vesicles, mucosal immunity, inflammatory bowel disease, gastrointestinal infections, lysosomal degradation, innate immune recognition
- MeSH terms
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Animals, Enterocolitis, Intestines, Listeriosis, Lysosomes, Muramidase, Symbiosis, Inflammatory Bowel Diseases, Protein Serine-Threonine Kinases, Mice, Knockout, Immunity, Mucosal, Paneth Cells, rab GTP-Binding Proteins, rab2 GTP-Binding Protein, Secretory Vesicles, Mice, Nod2 Signaling Adaptor Protein
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