Laboratory of Gut Inflammation and Infection Biology, Regional Centre for Biotechnology, Faridabad, India
Yesheswini Rajendran
Laboratory of Gut Inflammation and Infection Biology, Regional Centre for Biotechnology, Faridabad, India
Bhagyashree Srivastava
Departmnet of Bioscience and Biotechnology, Banasthali Vidyapith, Aliyabad, India
Manasvini Markandey
Department of Gastroenterology, All India Institute of Medical Sciences, Delhi, India
Vered Fishbain-Yoskovitz
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Gayatree Mohapatra
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Aamir Suhail
Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, United States
Shikha Chaudhary
Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
Shaifali Tyagi
Vaccine and Infectious Disease Research Center, Translational Health Science and Technology Institute, Faridabad, India
Subhash Chandra Yadav
Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
Amit Kumar Pandey
Vaccine and Infectious Disease Research Center, Translational Health Science and Technology Institute, Faridabad, India
Yifat Merbl
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Inflammation in ulcerative colitis is typically restricted to the mucosal layer of distal gut. Disrupted mucus barrier, coupled with microbial dysbiosis, has been reported to occur prior to the onset of inflammation. Here, we show the involvement of vesicular trafficking protein Rab7 in regulating the colonic mucus system. We identified a lowered Rab7 expression in goblet cells of colon during human and murine colitis. In vivo Rab7 knocked down mice (Rab7KD) displayed a compromised mucus layer, increased microbial permeability, and depleted gut microbiota with enhanced susceptibility to dextran sodium-sulfate induced colitis. These abnormalities emerged owing to altered mucus composition, as revealed by mucus proteomics, with increased expression of mucin protease chloride channel accessory 1 (CLCA1). Mechanistically, Rab7 maintained optimal CLCA1 levels by controlling its lysosomal degradation, a process that was dysregulated during colitis. Overall, our work establishes a role for Rab7-dependent control of CLCA1 secretion required for maintaining mucosal homeostasis.
