Ética y Legalidad

B y ta rg e tin g class II m o lecu les to en d o cy tic co m p artm en ts li prom otes its own destru ctio n . E ndocytic endoproteases degrade li in a stepw ise fashion. T he first tw o steps in li d eg rad atio n are carried out by endosom al aspartyl an d /o r cysteine p ro teases lik e cath ep sin s B and L, and resu lt in a - 1 0 kD li frag m en t th at com prises the N -term inus and ends w ith the CLIP region bound in

the class II groove. T he class Il/Ii nonam er is destroyed by these cleav ag e steps. N ext the - 1 0 kD, referred to as leu p ep tin -in d u ced p e p tid e (L IP ), b e c a u se tre a tm e n t o f cells w ith the p ro te a se in h ib ito r leupeptin leads to accum ulation of class Il-asso ciated LIP frag m e n ts (N eefjes and Ploegh, 1992), is further degraded to give rise to CLIP which is still bound to the peptide binding groove. The d e g ra d a tio n o f LIP is c ritic a l b ecau se by c leav in g o ff the N- te rm in a l c y to so lic p a rt fro m the C L IP p o rtio n M H C c lass II m o le c u le s are re le a s e d fro m th e e n d o so m al re te n tio n sig n a l lo calised in the li cytosolic dom ain (Loss and Sant, 1993; N eefjes and Ploegh, 1992) and can leave for the cell surface. The cleavage o f L IP c a n be r e p r e s s e d w ith m o r p h o li n u r e a - l e u c in e - h o m o p h en y lala n in e -v in y lsu lfo n e -p h en y l (LHV S) w hich is a h ig h ly specific in h ib ito r of C athepsin S p o inting to a p iv o tal role o f this p r o te a s e in g e n e ra tin g p e p tid e - b in d in g c o m p e te n t c la s s II m olecules and controlling the location o f class II m olecules ( P ie r r e and M ellm an, 1998; R iese et al., 1996). In terestin g ly , in co rtical th y m ic e p ith e liu m c a th e p sin L seem s to re p la c e c a th e p sin S (N ak ag aw a et al., 1998) thus im p o sin g tissue sp ecificity on the cleavage o f li and p ep tid e precursors. It is tem pting to speculate th a t tis su e -sp e c ific p ro te a se s lik e c a th e p sin L c o u ld hav e an in flu en ce on thym ic events like p o sitiv e and negative selection o f T cells (C ressw ell, 1998). A fter the fin al cleav ag e o f L IP the re su ltin g C L IP frag m en t now b locks the p ep tid e b in d in g groove and has to be rem oved p rio r to the binding of antigenic peptides. T h is re m o v a l is c a ta ly se d by the n o n -c la ssic a l M H C class II molecule HLA-DM and will be described in detail later.

A novel function as a protease in h ib ito r has been ascribed to the p41 fo rm o f in v a ria n t ch ain . As fa r as class . II fo ld in g and tra ffic k in g is co n ce rn e d p33 and p41 seem to be e q u iv a le n t

(S h a c h a r et al., 1995; T ak e su et a l., 1997) b u t e n h a n c e d presentation o f certain epitopes seem to be solely m ediated by the p41 form o f li (Fineschi et al., 1996; P eterson an d M iller, 1992). T he e x tra frag m en t p re se n t in p41 has b een d e m o n stra te d to function as an inhibitor of cathepsin L (Bevec et al., 1996; Fineschi et a l., 1996) th u s p re s e rv in g e p ito p e s th a t a re o th e rw is e destroyed by cathepsin L. It rem ains to be estab lish ed how these d iffe re n t lev els o f reg u la tio n by d iffe re n t iso fo rm s o f li and d iffe re n t cath ep sin s tie in w ith the g e n eral p ic tu re o f a n tig en presentation and the establishment of tolerance.