title: Role of RIP1 in physiological enterocyte turnover in mouse small intestine via nonapoptotic death.
abstract: Enterocyte shedding in the small intestine is often referred as an example of programmed cell death. However, little is known about the underlying mechanisms, although both apoptotic and nonapoptotic cell death have been suggested to play an important role. Here, we show by electron microscope that the majority of cells dying in the mouse small intestine do not display apoptotic characteristics. Chemical biological approach in vivo and in an organ culture showed that necrostatin-1 (Nec-1), an inhibitor of receptor-interacting protein 1 (RIP1, also called RIPK1), inhibited the shedding/nonapoptotic death of enterocyte, resulting in suppression of physiological enterocyte turnover. Moreover, RIP1 knockdown in vivo and RIP1 haploinsufficiency significantly suppressed physiological enterocyte turnover. Unlike Nec-1-sensitive (RIP1-dependent) cell death, so called necroptosis, which is also dependent on RIP3, physiological enterocyte turnover in RIP3-deficient mice was executed normally and still inhibited by Nec-1. As inhibition of the shedding/nonapoptotic death of enterocyte by Nec-1 resulted in suppression of crypt cell proliferation, the shedding process plays a dominant role over cell proliferation in maintaining homeostasis of enterocyte turnover. These results indicate that RIP1 plays a major role in physiological enterocyte turnover through a RIP3-independent nonapoptotic death mechanism in the mouse small intestine.
authors.affiliation: Department of Medical Genetics, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Tsujimoto
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D049109:Cell Proliferation; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D007093:Imidazoles; D007211:Indoles; C490620:Ralbp1 protein, mouse; C507699:necrostatin-1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse