Abstract
Herein, a set of optogenetic tools (designated LiPOP) that enable photoswitchable necroptosis and pyroptosis in live cells with varying kinetics, is introduced. The LiPOP tools allow reconstruction of the key molecular steps involved in these two non‐apoptotic cell death pathways by harnessing the power of light. Further, the use of LiPOPs coupled with upconversion nanoparticles or bioluminescence is demonstrated to achieve wireless optogenetic or chemo‐optogenetic killing of cancer cells in multiple mouse tumor models. LiPOPs can trigger necroptotic and pyroptotic cell death in cultured prokaryotic or eukaryotic cells and in living animals, and set the stage for studying the role of non‐apoptotic cell death pathways during microbial infection and anti‐tumor immunity.
Highlights
A set of optogenetic tools that enable receptor 1 (TNFR1),[4] followed by the successive activation of receptor-interacting photoswitchable necroptosis and pyroptosis in live cells with varying kinetics, protein kinase 1 and 3 (RIPK1/3) and the is introduced
Similar to death, is characterized by the activation of a series of cysteine- necroptosis and its specific effector molecule mixed lineage kinase domain like (MLKL), pyroptosis is aspartic proteases,[1] and plays a critical role in the primarily executed by members of the gasdermin protein family elimination of damaged cells to maintain tissue homeostasis.[2] (Gasdermin D, gasdermin D (GSDMD) and Gasdermin E, GSDME), which are Necrosis is generally regarded as a form of uncontrolled cell cleaved by activated caspases to promote its self-oligomerization death
Activated RIPK3 further phosphorylates the downstream pseudokinase MLKL at residues threonine and serine (T357-p/S358-p). These posttranslational modifications lead to the exposure of the N-terminal four helical bundle domain (4HBD) of MLKL (MLKL-NT) to cause plasma membrane (PM) rupture and necroptosis (Figure 1a).[5]
Summary
Upon death receptor activation (e.g., TNFR), necroptosis is initiated by the formation of a necrosome with RIPK1 and RIPK3 as two essential components. Oligomerized RIPK1 forms a platform to recruit RIPK3 and induce complex formation, with consequent auto-phosphorylation of RIPK3. Activated RIPK3 further phosphorylates the downstream pseudokinase MLKL at residues threonine and serine (T357-p/S358-p). These posttranslational modifications lead to the exposure of the N-terminal four helical bundle domain (4HBD) of MLKL (MLKL-NT) to cause PM rupture and necroptosis (Figure 1a).[5] We first set out to reconstruct the necroptotic pathway via photo-modulation of necrosome formation. We fused RIPK1 to an optical multimerizer, the N-terminal photolyase-homologous region of CRY2 (CRY2PHR),[14b] which contains a flavin adenine dinucleotide (FAD) cofactor and undergoes monomer-to-oligomer
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