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Rab11FIP1-deficient mice develop spontaneous inflammation and show increased
susceptibility to colon damage.
Authors Rathan-Kumar S, Roland JT, Momoh M, Goldstein A, Lapierre LA, Manning E,
Mitchell L, Norman J, Kaji I, Goldenring JR
Submitted By Submitted Externally on 10/5/2022
Status Published
Journal American journal of physiology. Gastrointestinal and liver physiology
Year 2022
Date Published 9/1/2022
Volume : Pages 323 : G239 - G254
PubMed Reference 35819177
Abstract The small GTPase, Rab11a, regulates vesicle trafficking and cell polarity in
epithelial cells through interaction with Rab11 family-interacting proteins
(Rab11-FIPs). We hypothesized that deficiency of Rab11-FIP1 would affect mucosal
integrity in the intestine. Global Rab11FIP1 knockout (KO) mice were generated
by deletion of the second exon. Pathology of intestinal tissues was analyzed by
immunostaining of colonic sections and RNA-sequencing of isolated colonic
epithelial cells. A low concentration of dextran sodium sulfate (DSS, 2%) was
added to drinking water for 5 days, and injury score was compared between
Rab11FIP1 KO, Rab11FIP2 KO, and heterozygous littermates. Rab11FIP1 KO mice
showed normal fertility and body weight gain. More frequent lymphoid patches and
infiltration of macrophages and neutrophils were identified in Rab11FIP1 KO mice
before the development of rectal prolapse compared with control mice. The
population of trefoil factor 3 (TFF3)-positive goblet cells was significantly
lower, and the ratio of proliferative to nonproliferative cells was higher in
Rab11FIP1 KO colons. Transcription signatures indicated that Rab11FIP1 deletion
downregulated genes that mediate stress tolerance response, whereas genes
mediating the response to infection were significantly upregulated, consistent
with the inflammatory responses in the steady state. Lack of Rab11FIP1 also
resulted in abnormal accumulation of subapical vesicles in colonocytes and the
internalization of transmembrane mucin, MUC13, with Rab14. After DSS treatment,
Rab11FIP1 KO mice showed greater body weight loss and more severe mucosal damage
than those in heterozygous littermates. These findings suggest that Rab11FIP1 is
important for cytoprotection mechanisms and for the maintenance of colonic
mucosal integrity.NEW & NOTEWORTHY Although Rab11FIP1 is important in membrane
trafficking in epithelial cells, the gastrointestinal phenotype of Rab11FIP1
knockout (KO) mice had never been reported. This study demonstrated that
Rab11FIP1 loss induces mistrafficking of Rab14 and MUC13 and decreases in
colonic goblet cells, resulting in impaired mucosal integrity.


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