CRISPR-Cas systems detect and defend prokaryotes from mobile genetic elements such as plasmids and bacteriophage. Recently, a subset of Type VI CRISPR-Cas systems, which use the RNA-guided RNase Cas13, have been found to include underexamined putative membrane proteins that have unclear roles in Cas13-mediated phage defense. My lab is interested in further understanding Cas13 biology including the role and the mechanism by which these putative membrane proteins modulate CRISPR-Cas immunity. To this end, we recently discovered that CRISPR-Csx28, of Type VI-B2 systems, forms a membrane pore-channel that acts to slow cellular metabolism upon Cas13b-sensed viral infection, which results in a dramatic enhancement of Cas13b anti-viral defense. I will present our work that uses a combination of high resolution cryo-electron microscopy, biochemistry, and bacteriophage assays, to demonstrate that the drastic enhancement of anti-viral defense is attributed to formation of Cas13-activated homo-octameric Csx28 membrane pore-channels. We show that when Cas13 senses bacteriophage infection, Csx28 pores are activated and depolarize the bacterial cell membrane, which subsequently results in a transient loss of cellular metabolism. These data reveal an unprecedented mechanism by which Csx28 acts as a downstream (Cas13b-activated) effector protein that uses membrane perturbation as an anti-viral defense strategy, highlighting a potentially general and underappreciated aspect of CRISPR-Cas systems. Beyond this specific system, I will share our progress on expanding these efforts to look at other membrane-protein containing CRISPR-Cas systems, as well as other anti-phage defense systems that contain membrane proteins.