资源环境科技发展态势分析平台

The CRISPR system in bacteria and archaea provides adaptive immunity against mobile genetic elements. Type III CRISPR systems detect viral RNA, resulting in the activation of two regions of the Cas10 protein: an HD nuclease domain (which degrades viral DNA)(1,2) and a cyclase domain (which synthesizes cyclic oligoadenylates from ATP)(3-5). Cyclic oligoadenylates in turn activate defence enzymes with a CRISPR-associated Rossmann fold domain(6), sculpting a powerful antiviral response(7-10) that can drive viruses to extinction(7,8). Cyclic nucleotides are increasingly implicated in host-pathogen interactions(11-13). Here we identify a new family of viral anti-CRISPR (Acr) enzymes that rapidly degrade cyclic tetra-adenylate (cA(4)). The viral ring nuclease AcrIII-1 is widely distributed in archaeal and bacterial viruses and in proviruses. The enzyme uses a previously unknown fold to bind cA(4) specifically, and a conserved active site to rapidly cleave this signalling molecule, allowing viruses to neutralize the type III CRISPR defence system. The AcrIII-1 family has a broad host range, as it targets cA(4) signalling molecules rather than specific CRISPR effector proteins. Our findings highlight the crucial role of cyclic nucleotide signalling in the conflict between viruses and their hosts.

LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach(1), but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5(+) intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway(2). However, the contribution of pyloric LGR5(+) stem cells to gastric cancer following dysregulation of the WNT pathway-a frequent event in gastric cancer in humans(3)-is unknown. Here we use comparative profiling of LGR5(+) stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5(+) compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5(+) cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic.

AQP5 is identified as a marker for pyloric stem cells in humans and mice, and stem cells in the AQP5(+) compartment are shown to be a source of invasive gastric cancer in mouse models.