LATE EVENTS IN THE INTRACELLULAR SORTING OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II MOLECULES ARE REGULATED BY THE 80-82 SEGMENT OF THE CLASS-II BETA-CHAIN
Lj. Tan et al., LATE EVENTS IN THE INTRACELLULAR SORTING OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II MOLECULES ARE REGULATED BY THE 80-82 SEGMENT OF THE CLASS-II BETA-CHAIN, European Journal of Immunology, 27(6), 1997, pp. 1479-1488
The molecular mechanisms that regulate sorting of major histocompatibi
lity complex (MHC) class II molecules into the endocytic pathway are p
oorly understood. For many proteins, access to endosomal compartments
is regulated by cytosolically expressed sequences. We present evidence
that a sequence in the lumenal domain of the MHC class II molecule re
gulates a very late event in class II biogenesis. Class II molecules c
ontaining single amino acid changes in the highly conserved 80-82 regi
on of the beta chain were introduced into invariant chain (Ii)-negativ
e fibroblasts with wild-type alpha chain, and the derived transfectant
s were analyzed biochemically. Using an endosomal isolation technique,
we have quantified the level of class II molecules expressed in endoc
ytic compartments and found that in the absence of Ii, approximately 1
5 % of total cellular class II molecules can be isolated from endosoma
l compartments. Mutation at position 80 enhances this localization, wh
ile changes at positions 81 and 82 ablate class II expression in endos
omal compartments. In addition, we have evaluated whether the induced
changes in intracellular distribution of class II molecules were due t
o alterations in early biosynthetic events, indicative of misfolding o
f the molecules, or to modulation of later trafficking events more lik
ely to be a consequence of the modulation of a specific transport even
t. Despite the dramatic effects on endosomal localization induced by t
he mutations, early biosynthetic events and maturation of class II wer
e unaffected by the mutations. Collectively, our data argue that late
trafficking events that control the ability of the class II molecule t
o access antigens is regulated by the 80-82 segment of the MHC class I
I beta chains.