Cullin 4b Complex Targets IRGM1 to Regulate Intestinal Stem Cell Stemness and Niche

Abstract

Hierarchical organization of intestine relies on the self-renewal and tightly regulated differentiation of intestinal stem cells (ISCs). Although signals like Wnt are known to sustain the continued renewal by maintaining ISCs activity, molecular mechanisms underlying ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (CUL4B) in intestine regulation. CUL4B is mainly expressed at ISCs zone. Deletion of Cul4b led to impaired intestinal cell components due to reduced self-renewal of ISCs and a downregulated Wnt signals. Cul4b-null mice exhibited impaired Paneth cells, ISC niche and aggravated intestinal inflammation. Mechanistically, CRL4B complex ubiquitylates immunity-related GTPase family M member 1 (IRGM1) at K270. Impaired intestinal function caused by CUL4B deletion is mediated by upregulation of its substrate IRGM1. Our results suggest CUL4B functions to target IRGM1 as a novel regulator of ISC stemness and niche. Hierarchical organization of intestine relies on the self-renewal and tightly regulated differentiation of intestinal stem cells (ISCs). Although signals like Wnt are known to sustain the continued renewal by maintaining ISCs activity, molecular mechanisms underlying ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (CUL4B) in intestine regulation. CUL4B is mainly expressed at ISCs zone. Deletion of Cul4b led to impaired intestinal cell components due to reduced self-renewal of ISCs and a downregulated Wnt signals. Cul4b -null mice exhibited impaired Paneth cells, ISC niche and aggravated intestinal inflammation. Mechanistically, CRL4B complex ubiquitylates immunity-related GTPase family M member 1 (IRGM1) at K270. Impaired intestinal function caused by CUL4B deletion is mediated by upregulation of its substrate IRGM1. Our results suggest CUL4B functions to target IRGM1 as a novel regulator of ISC stemness and niche.