Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for signaling

• DOI: 10.1073/pnas.1115091109
• Publication Date: 2012-05-20T13:03:27Z
• Authors: Alejandra Garcia-...; François-Xavier G...; Mélanie Müller; Florent Toscano; Marcella Flores; Aurianne Lescure; Elaine Del Nery; Philippe Benaroch
• Keywords: TLR3; Cathepsin H

Toll-like receptor (TLR) 3 is an endosomal TLR that mediates immune responses against viral infections upon activation by its ligand double-stranded RNA, a replication intermediate of most viruses. TLR3 expressed widely in the body and activates both innate adaptive systems. However, little known about how intracellular trafficking maturation are regulated. Here we show newly synthesized endogenous transported through ER Golgi apparatus to endosomes, where it rapidly cleaved. protein expression up-regulated own ligand, leading accumulation cleaved form. In agreement with proposed role as transporter, UNC93B1 required for cleavage signaling. Furthermore, signaling sensitive cathepsin inhibition. Cleavage occurs between aa 252 346, results functional signals activation. A truncated form lacking N-terminal 345 also from acidic compartments response Screening human family RNA interference identified cathepsins B H key mediators processing. Taken together, our data indicate proteolytic processing essential function, suggest mechanism tight control thus immunity.