Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι
Yuki Nakanishi,
Miguel Reina-Campos,
Naoko Nakanishi,
Victoria Llado,
Lisa Elmen,
Scott Peterson,
Alex Campos,
Surya K. De,
Michael Leitges,
Hiroki Ikeuchi,
Maurizio Pellecchia,
Richard S. Blumberg,
Maria T. Diaz-Meco,
Jorge Moscat
Affiliations
Yuki Nakanishi
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Miguel Reina-Campos
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Naoko Nakanishi
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Victoria Llado
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Lisa Elmen
Bioinformatics and Structural Biology Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Scott Peterson
Bioinformatics and Structural Biology Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Alex Campos
Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Surya K. De
Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
Michael Leitges
Biotechnology Centre of Oslo, University of Oslo, 0316 Oslo, Norway
Hiroki Ikeuchi
Department of Surgery, Hyogo College of Medicine, Nishinomiya 663-8131, Japan
Maurizio Pellecchia
Division of Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Avenue, Riverside, CA 92521, USA
Richard S. Blumberg
Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Maria T. Diaz-Meco
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Jorge Moscat
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5+ stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here, we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation. The selective inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn’s disease. Kaplan-Meier survival analysis of colorectal cancer (CRC) patients revealed that low PRKCI levels correlated with significantly worse patient survival rates. Therefore, PKCλ/ι is a negative regulator of intestinal inflammation and cancer through its role in Paneth cell homeostasis.
