The p41 isoform of invariant chain is a chaperone for cathepsin L

The p41 splice variant of major histocompatibility complex (MHC) class II-a ssociated invariant chain (Ii) contains a 65 aa segment that binds to the a ctive site of cathepsin L (CatL), a lysosomal cysteine protease involved in MHC class II-restricted antigen presentation. This segment is absent from the predominant form of Ii, p31. Here we document the in vivo significance of the p41-CatL interaction. By biochemical means and electron microscopy, we demonstrate that the levels of active CatL are strongly reduced in bone marrow-derived antigen-presenting cells that lack p41. This defect mainly c oncerns the mature two-chain forms of CatL, which depend on p41 to be expre ssed at wild-type levels. Indeed, pulse-chase analysis suggests that these mature forms of CatL are degraded by endocytic proteases when p41 is absent . We conclude that p4l. is required for activity of CatL by stabilizing the mature forms of the enzyme. This suggests that p4l is not merely an inhibi tor of CatL enzymatic activity, but serves as a chaperone to help maintain a pool of mature enzyme in late-endocytic compartments of antigen-presentin g cells.