Rab11a is required for apical protein localisation in the intestine
Tomoaki Sobajima1, Shin-Ichiro Yoshimura2, Tomohiko Iwano2
1Department of Cell Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
Insights
The small GTPase Rab11a is crucial for intestinal cell function. Its absence causes protein mislocalisation, affecting nutrient uptake and leading to early death in mice.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- The small GTPase Rab11 is vital for protein recycling and polarized transport in epithelial cells and neurons.
- Rab11a's specific role in intestinal function and its in vivo interactions are not fully understood.
Purpose of the Study:
- To investigate the function of Rab11a in vivo using conditional knockout mice.
- To elucidate the role of Rab11a in protein localisation and transport within the intestine.
- To explore functional relationships between Rab11a, Rab8a, and myosin Vb.
Main Methods:
- Generation of conditional knockout mice lacking Rab11a.
- Analysis of intestinal architecture and protein localisation in knockout mice.
- Comparison with Rab8a knockout mice and a patient with myosin Vb mutation.
Main Results:
- Intestine-specific Rab11a knockout mice exhibit embryonic lethality and early postnatal death.
- Apical proteins mislocalise to the basolateral membrane in knockout intestines, impacting nutrient uptake.
- Microvilli abnormalities and mislocalisation of Rab8a are observed in Rab11a knockout mice.
Conclusions:
- Rab11a is essential for apical protein localisation in the intestine.
- Rab11a, Rab8a, and myosin Vb are functionally interconnected in vivo.
- Disruption of Rab11a function leads to severe intestinal defects and mortality.
Abstract:
The small GTPase Rab11 plays an important role in the recycling of proteins to the plasma membrane as well as in polarised transport in epithelial cells and neurons. We generated conditional knockout mice deficient in Rab11a. Rab11a-deficient mice are embryonic lethal, and brain-specific Rab11a knockout mice show no overt abnormalities in brain architecture. In contrast, intestine-specific Rab11a knockout mice begin dying approximately 1 week after birth. Apical proteins in the intestines of knockout mice accumulate in the cytoplasm and mislocalise to the basolateral plasma membrane, whereas the localisation of basolateral proteins is unaffected. Shorter microvilli and microvillus inclusion bodies are also observed in the knockout mice. Elevation of a serum starvation marker was also observed, likely caused by the mislocalisation of apical proteins and reduced nutrient uptake. In addition, Rab8a is mislocalised in Rab11a knockout mice. Conversely, Rab11a is mislocalised in Rab8a knockout mice and in a microvillus atrophy patient, which has a mutation in the myosin Vb gene. Our data show an essential role for Rab11a in the localisation of apical proteins in the intestine and demonstrate functional relationships between Rab11a, Rab8a and myosin Vb in vivo.
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