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I n v ar ia nt chain is a tra n sm em b ra n e glycoprotein of 33Kd - 43 Kd which, unlik e the MHC II, is a no n- p o ly mo rp h ic species. Four li isof orms have been ide nt ifi ed to date (Cresswell, 1994; Gorvel et al, 1995). The core h um an forms of li which account for almost 90% of in tra c el lu la r li, are the p33 and p41 species. In turn, the p33 species prevails over p41 as the mos t co m m o n li isoform (Fineschi et al, 1995; W a r m e rd a m et al, 1996). A lt e r n a t e splicing introduces an add itional exon into the p33 gene, adds an ot he r 64 amino acid sequence to give the p41 li isoform. The m in o r li species, p35 and p43, arise from the addition of a 16 amino acid seque nce to the C-te rm ian l portions of p33 and p41 resp ec ti ve ly (C ressw ell, 1994; F in es ch i et al, 1995). The p33 li iso fo rm is a ~ 200 amino acid residue, gl yc o sy lat ed protein of which residues 30-60 form the tr a n sm em b r an e reg io n while residues 1-29 form the cytopl asm ic tail. The re m ai n in g C-

ter minal por tion forms the lumenal domain of p33 li (R o m ag n o li & Germain, 1994; Gorvel et al, 1995). Each of these regions plays a role in the re gul atio n of MHC II tra nsport and peptide loading. li plays three crucial roles in the life cycle of an MHC II molecule, namely: En s ur ing correct assembly of the MHCII com pl ex in the ER, rete nt ion of M HC II in the endocytic pathway, and targeting of the MHC II c o m p le x to the pr oc ess in g com partment.

li is synthesised, along with the OC and (3 MHC II chains, in the ER in

t rimeric form. Nas cen t MHC II comp lexe s form as non om er ic co m p le xe s ; trimers of a trimer, based around three li m olecules as a b ac kb o n e (Roche & Cresswell, 1991; Cresswell, 1994). A region betwe en re sid ues 84 and 105 of the lumenal domain is thought to regulate this asse mb ly (R o m ag n ol i

et al, 1994). Studies in the human APC lines revealed that m u t at i on s in this region result in the presence of surface MHC II m ol ec u le s with signif ica nt ly altered formation. The same ph en o m en on is seen in li chain de ficie nt mice (Viville et al, 1993; Bodm er et al, 1994). This di st in ct set of class II m olecules are still however, able to bind and pr es en t p ept id e. In the absence of class II association, li trimers accu mu lat e in the RER (Marks et al, 1990). The presence of li in the ER prevents the bi n d i n g of peptides from the cytoplasmic pool, des tined for class I as so ci at io n, from

bi ndi ng the imm atu re a/(3 class II dimer. F ol lo w in g f o rm at io n of the

a / | 3 / I i com plex , the nascent MHC II no nomeric com pl ex moves to the golgi

comple x where further glycosylation and syalation occur ( Cr es sw el l, 1994, Ar neson & Miller, 1995). MHC I-peptide ag com pl exe s are su b je c te d to an identical treatment, prior to transp or t to the cell surface. The MH C II comp lex, via targeting signals in the cyto plasmic tail of li, is d iv e r te d from such a ‘d e f a u l t ’ transp or t route, to the endosomal pathway. Such t ar get ing signals have been located to residues 7 to 8 and 15 to 17 of the c y t o p la sm ic domain of li (Anderson et al, 1993; Arneson & Miller, 1995). Th e region

spann ing residues 84 to 105 of the lumenal domain is also likely to

regul ate the transp or t of the a/(3/Ii complex from the ER to the e n d o s om e s

via the golgi complex (Romagnoli & Germain, 1994). The add it io nal 16 cyt opl asm ic residues of the P35 and p41 li isoforms m os t p ro b ab l y also conta in a golgi reten tion signal (Lotteau et al, 1990, W a r d e r d a m et al,

1996).

li regulates the tra nsport of the MHC II compl ex into the antigen pr o ce ss in g com par tm en t by a variety of m echanisms. Lack of e n d os o m a l

tar get ing signal has been shown to result in an ac cu m u lat io n of a / p / I i

co m pl ex es on the surface of APC (Pieters et al, 1993). F ur th er to such sig naling me cha ni sms however, li also appears to re gulate MH C II t ra nsp or t at an additional level. There is evidence to suggest that the quan tity of li molecules present within APC det er m ine to which pr o c e ss i n g

co m p ar t m e n t the a / p / I i complex is targeted (Ram agn ol i et al, 1993). At

low li levels, the tra nsport of OC/p/Ii com pl exe s into later endo cyt ic

str uctures is delayed. Class II com pl exe s accu mu lat e with en d o cy t o s ed mate rial in early end osomal co mp ar tm e n ts under such con d it io n s.

Conv erse ly, the majority of a / p / I i complex es are dire cte d to later str uctures when li exp ression is high.

The p41 isoform of li has recently attracted interest, briefly di s c u s s e d in s e c t i o n 1.5.2.3, as a possible regulator of li pro teolys is (Bevec et al, 1995, F in es ch i et al, 1995; Takaesu et al, 1995). p41 appears to i n hi b it li de gr ad at io n at a par tic ula r stage in its proteolysis by s pe cif ic all y bi nd in g to cathe ps in L, thus pr eventing this cysteine pr o te in a se from p r o c e s s i n g li further. As each isoform of li becomes more well c ha r ac te r is ed , it is b e c o m i n g evident that each appears to play a subtly d ist in ct role in the re g ul at io n of MHC II tra nsport and pepti de binding.