Chemistry and functional role of the invariant chain

Chemistry and functional role of the invariant chain

Peter Cresswell

Yale University School of Medicine, New Haven, Connecticut, USA

The invariant chain has two critical properties that regulate the function of the class II glycoproteins with which it associates. It prevents class II molecules from binding antigenic peptides during the early stages of their assembly and transport, and it contains a signal that drives the assembled class If-invariant chain complex to an endocytic compartment. Dissociation of the invariant chain in this compartment is believed to generate class II

molecules capable of binding antigenic peptides.

Current Opinion in Immunology 1992, 487-92

Introduction

The function of MHC glycoproteins is to bind peptides derived from foreign antigens and to display them on cells for recognition by T lymphocytes. Class I molecules (HLA-A, B and C in humans; H-2 K, D and L in mice) bind peptides mainly derived from cytosolic proteins and are critical for the recognition of viral antigens by cytotoxic CD@ T cells. Class II molecules (HIA-DR, DQ and DP in humans; H-2 I-A and I-E in mice) bind peptides derived from extracellular protein antigens that have been internalized by antigen-presenting cells, such as macrophages or B cells. These peptide-class II MHC complexes stirn- ulate antigen-specific CD4 + T cells. The ability of class I and class II MHC glycoproteins to discriminate between different subgroups of antigenic peptides is in part reg- ulated by the interaction of class II molecules with the invariant chain.

Invariant chain structure

A number of forms of invariant chain exist, deiined by the primary amino acid sequence (Fig. 1). The major form is a glycoprotein of 31000-33000 daltons (p33). This molecule is a type II membrane glycoprotein, with a short 30 residue amino-terminal cytoplasmic domain, a typical hydrophobic transmembrane region of 256 amino acids, and a carboxy-terminal region of 160 amino acids bearing two N-linked glycans [1,2,]. The transmembrane region serves as a non-cleavable signal sequence that is responsible for translocation of the invariant chain into the endoplasmic reticulum [3]. In humans an alternative form of the invariant chain, ~35, results from initiation of translation at an AUG codon upstream of that used to generate p33 and has an amino-terminal cytoplasmic extension of an additional 16 residues [4,5]. This form does not exist in mice. Both mice and humans, however, possess an additional form of the variant chain that re-

suits from alternative splicing of an additional exon. This generates a third species, ~41, with a 64 amino acid in- sertion between residues 192 and 193 of the p33 form of the invariant chain [4-6]. The additional sequence is homologous to repeat sequences in thyroglobulin and bears two additional N-linked glycans [7]. Finally, in humans the alternative initiation of translation that gives rise to p35 also gives rise to a form of p41 that has a simi- larly elongated cytoplasmic domain [4,5]. This species is called p43.

In addition to the acquisition of the N-linked glycans, the invariant chain undergoes a number of other post-translational modifications. These include the addition of a chondroitin-sulfate side chain to a small fraction of the molecules [8]. Site-directed mutagenesis of a conserved serine residue (position 201 in the mouse, homologous to residue 202 in humans) eliminates this modification [9]. Additional reported modifications are phosphotyla- tion [lo], and palmitylation of the cysteine residue in the cytoplasmic tail [ 111, and the addition of at least two o-linked glycans [ 121.

In the absence of association with class II glycoproteins, the human invariant chain is trimeric [ 131. This is true for invariant chain synthesized in mutant class II MHC-negative cell lines, and also for free invariant chain present in excess in normal B-cell lines. An 18kD fragment of the invariant chain produced by proteinase K digestion, which lacks the cytoplasmic domain and transmembrane region, is also trimeric [13], which suggests that trimerization is a function of the carboxy-terminal lumenal region of the molecule. Mixed trimers of p33 and p35 can be found in addition to p33 homotrimers. Co-transfection into HeIa cells of a cDNA expression vector encoding the p41 and p43 forms, together with a second vector encoding only the p33 form, has been used to show that p41/p43 can associate with ~33, although the precise sto- ichiometry of such complexes has not been determined (C Iamb and P Cresswell, unpublished data).

Abbreviations ER-ndoplasmic reticulum; MHC-major histocompatibility complex.

@ Current Biology Ltd ISSN 0952-7915 87

88 Antigen recognition

P33 H*N I] COO”

p35 H2N 21 COOH

?? p4’ H2N 1 ] COOH

?? ~43 HzN 1 1 1 COOH

Structure of the class II MHC-invariant chain

complex

Class II molecules on the surface of cells exist as a het- erodimer of a- and P-subunits. Both subunits are encoded by linked genes in the MHC and are type I membrane glycoproteins with short carboxyl-terminal cytoplasmic domains. It is assumed, by analogy with the known class I structure [ 141, that the membrane distal domains of the u- and l3subunits form a peptide-binding site consisting of a platform of eight strands of p-pleated sheet with two a-helices forming the boundaries [ 151. A combination of chemical cross-linking, gel filtration and sedimentation velocity techniques has been used to study the structure of the HLADR-invariant chain complex [l&*1. The results suggest that the complex contains three a-subunits, three j3subunits and three invariant chain molecules. Because the invariant chain is trimeric in the absence of class II associations, it seems likely that the complex may consist of a core invariant chain trimer associated with three af3 dimers. Class II af3 dimers, which are capable of binding peptides, can be released from HLADR-invariant chain complexes either

Fig. 1. The four basic forms of the human invariant chain. The p41 and p43 forms differ from the p33 and p35 forms by the inclusion of a 64 amino acid in- sertion derived by the splicing of an alternate exon. The ~35 and p43 forms differ from the p33 and p41 forms by the addition of a 16 amino acid amino- terminal extension that results from alternative translational initiation. 7 T,N- linked glycans.

by partial denaturation with low concentrations of SDS [17] or by proteolysis of the invariant chain in the complex with cathepsin B [ 18*] . This indicates that the a- and P-subunits are probably associated as heterodimers in the nonameric complex. The Stokes’ radius of the ap- subunit-invariant chain complex (72@ is only slightly larger than that of the invariant chain trimer (67A), although the molecular weights differ by threefold (270 kD versus 90kD [l&*1). This suggests that the invariant chain trimer may have an extended conformation com- pared to a more compact, globular structure for the class II-invariant chain complex (Fig. 2).

Although the region of the invariant chain that interacts with the ap dimer is not precisely known, the 18 kD lumenal fragment generated by proteinase K digestion remains associated with the class II molecule [ 191. A 25 kD fragment, which retains the cytoplasmic and transmembrane regions and is induced by incubating B-cell lines in leupeptin (see below), also remains class II-associated [ 201. The region of overlap between these fragments, compris- ing approximately the central third of the molecule and including the two N-linked glycans, presumably contains the region that binds to the a-p dimer.

I Fig. 2. Schematic views of the postulated structures of invariant chain trimers and the aeinvariant chain complex. The illustrations represent an overhead view of the molecules, and attempt to portray the invariant chain as an extended structure associated with more globular ap dimers. This may explain the similarity in Stokes’ radii in spite of the threefold difference in molecular weight between the two molecules. I, invariant chain; a, a-chain; p, P-chain.

Chemistry and functional role of the invariant chain Cresswell 89

Because the up-subuni-invariant chain complex con- talns three cl@ dimers it is possible that different up dimers might be contained in the same nine-chain structure. Preliminary evidence for such association has been obtained in human cell lines transfected with mouse class II genes. A DR7positive cell line also expressing I-Ak appears to contain class II-invariant chain complexes with both I-A and DR CL- and P-subunits ( J. Riberdy and P. Cresswell, unpublished data).

Biosynthesis and transport of the class II- invariant chain complex

Recent studies combining cross-linking with pulse-chase analysis have shown that invariant chain trimerization occurs within 5min and prior to its association with a- and f&chains (C. Iamb and P. Cresswell, submitted for publication). Evidence from transfected cells expressing invariant chain with an u-chain alone or P-chain alone suggests that the invariant chain can associate with each independently [ 211. However, we have found that addition of successive af3 dimers to the invariant chain trimer appears to occur in a stepwise manner. Trimers lacking associated class II molecules are retained in the endoplasmic reticulum (ER) [13,22*-l but class II association provides a signal for transport, or, more accurately, inacti- vates a signal for retention (see below). Within 3G60 min following assembly the complex traverses the Golgi. This may be determined by the acquisition of sialic acid [ 231. Early experiments showed that transit through the Golgi precedes invariant chain dissociation and cell-surface expression by 1.5-2 h, suggesting a prolonged residence period in a post-Go@ compartment [ 24-261.

The exocytic route followed by the class II-invariant chain complex is connected to the endocytic pathway. Neuraminidase, either chemically conjugated to transfer- rin [27] or alone in high concentrations [ 261, can de- sialylate the glycans of class II-associated intracellular invariant chain following its internalization. Endocytic markers, such as inlluenza virus, colocalize in acidic endosomes with class II molecules and invariant chain when internalized by class II-positive HeIa cell tranfec- tams [22**,28**]. Electron microscopic studies of class II-invariant chain localization in human B-cell lines has proved somewhat controversial. Two separate studies agree on the basic finding that class II molecules are found in compartments accessible to the endocytic path way, but differ on precisely where the interaction occurs. One study suggests that it occurs in a post-Go@ compartment related to lysomes, on the basis of the presence of lysosomal markers [29”]. In a previous study, B-cell lines were found to internalize surface immunoglobulins into early endosomes containing class II molecules and invariant chain [30]. The reasons for these apparently disparate results are unclear, but overall the experiments support the hypothesis that antigens are internalized in such a way that they, and perhaps peptides generated from them, are readily accessible to intracellular class II molecules.

Endocytic vesicles identified by electron microscopy in B- cell lines that contain class II-invariant chain complexes also contain cathepsins B and D [ 301. This is consistent with observations suggesting that proteolysis is involved in the release of class II up dimers from the invariant chain. Incubation of human B-cell lines with leupeptin, a sulfhydryl proteinase inhibitor that inhibits cathepsin B, induces the accumulation of HLADR complexes containing a 25kD fragment of the invariant chain, termed leupeptin-induced protein, or LIP [20]. Presumably, in the absence of leupeptin, continuing proteolysis would lead to further degradation of the invariant chain and release of c$ dimers, as has been observed in vitrowhen c&nvariant chain complexes are treated with cathepsin B [18*].

The c@ dimers released following in viva invariant chain dissociation are more stable than those associated with invariant chain. Class II dimers associated with invariant chain dissociate into monomers in SDS at room tempera- ture whereas mature C@ dimers are resistant to SDS treat- ment unless heated [ 31,32**], This stability may correlate with peptide binding because antigenic peptides remain associated with HI&DR up dimers in SDS [33] and high concentrations of protein antigens added exogenously to antigen-presenting cells can accelerate the formation of stable dimers [ 32**].

The functional role of the invariant chain

Observations of class II biosynthesis suggest a model in which class II-invariant chain complexes are directed to an acidic, proteolytically active, endosomal compartment. Here, internalized protein antigens are delivered and degraded into peptides. In addition, the invariant chain is degraded and class II C$ dimers are released, bind peptides for which they have a sufficiently high alfinity, and transport them to the cell surface for T-cell recognition. This model leads to a number of questions. First, why do class II molecules fail to bind peptides earlier in transport, as appears to be the case for class I molecules? Second, what is responsible for the endosomal targeting of the class II invariant chain complexes? Third, how do the endosomally released up dimers get to the surface? Although the answer to the latter question remains unknown, it is clear that the answers to the first two lie in specific functional properties of the invariant chain.

Purified class II c$ dimers can specifically bind antigenic peptides in vitro [33_35]. Purified class II-invariant chain complexes, in contrast, are unable to bind peptides [ 171. Mild denaturation with low concentrations of SDS [ 171, or proteolysis of the invariant chain in the complex with cathepsin B [ 18.1, releases crfi dimers that bind antigenic peptides extremely well. In addition, soluble invariant chain, secreted by cells transfected with cDNA vectors encoding an amino-terminally deleted product, appears to block the in vitro presentation of peptides to specific CD4+ T cells by antigen-presenting cells [21]. Thus, the association of invariant chain with class II molecules in the early stages of assembly and transport is thought to


prevent them from binding inappropriate peptides. Fol- lowing transport through the Go@, endosomal proteolysis of the invariant chain releases ‘empty’ $I dimers that then associate with peptides either generated in endosomes or perhaps transported there from lysosomes [361. The signal that delivers class II-invariant chain complexes to endosomes lies in the amino-terminal cytoplasmic region, as does the signal responsible for retaining invariant chain in the ER until class II association occurs. The latter property is associated with the 16 residue amino terminal extension of p35 (Fig. 1). Transfected cells expressing only ~35, synthesized from cDNA expression vectors in which the ATG codon initiating p33 translation has been mutated, retain p35 in the ER [28**,37**]. Transfected cells expressing only p33, synthesized from similar vectors where the ATG codon initiating p35 synthesis has been mutated, express invariant chain in well-delined cytoplasmic vesicles [ 28**,37**]. These have been defined as endosomes by one group [37**1 and suggested to be autophagosomes by another [28**]. Work in our own laboratory suggests that these vesicles are in fact acidic endosomes, deiined by their accessibility to internalized iniluenza virus (C Iamb and P Cresswell, unpublished data). Interestingly, mutant cell lines expressing both p33 and p35 without class II molecules retain invariant chain in the ER [ 131, as do transfected HeIa cells expressing both forms [22**]. This appears to be largely because of the formation of mixed trimers of p33 and p35 and the dominance of the ER retention signal encoded in the cytoplasmic extension of ~35. Mouse invariant chain is also largely retained in the ER in the absence of class II association, even though the p35 form does not exist in mice [38]. The nature of the retention signal in the mouse is unknown. Mutant cDNA constructs in which 15 or more amino acids in the amino-terminal region of the invariant chain are further deleted are cell-surface expressed in transfec- tants [28**,37**]. More speciiically, it appears that an endosomal targeting signal is encoded between residues 11 and 15 of the cytoplasmic region of p33 [37**]. In normal circumstances one presumes that the ER retention signal is negated by the ap association that initiates transport whereas the endosomal targeting sequence remains accessible. This sequence may Interact with an accessory protein that delivers the class II-invariant chain complex to the endosome, but the precise mechanism remains unknown. Transfection experiments show that even in invariant chain-negative cells, class II CL- and P-subunits do associate into dimers [39,40]. Transport to the cell surface can occur, although it is impaired to a variable extent de- pending on the specific ctp pair being expressed [41*,42], and prior association with the invariant chain appears critical for the binding of certain conformationally sensi- tive monoclonal antibodies to class II molecules, implying a role for invariant chain in class II folding [43]. How- ever, class II dimers do not concentrate in endosomes when expressed in the absence of invariant chain. This is likely to be because they follow the normal constitutive pathway taken by the majority of glycoproteins to the cell

surface, although it is possible that they are transported to the cell surface via endosomes but are not retained there in the absence of invariant chain.

Conclusions

The predicted basic structure of the class II invariant chain complex, an invariant chain trimer as a core with three associated aP dimers, seems sound. Clearly, however, refinement of the structural model, perhaps by ob- taining the x-ray crystal structure of a water-soluble invariant chain derivative or even of the class II-invariant chain complex, is a major goal. The two most important functions of the invariant chain, the prevention of peptide binding in the early stages of transport and di rection of class II molecules to endosomes, also are well established. However, it is important to uncover the basic molecular and mechanistic details of these functions. In- variant chain may prevent peptide binding by interacting with class II molecules in the binding groove, essentially acting as a competitive inhibitor. Alternatively, the mechanism may be more subtle, involving a conformational modification of the class II dimer which prevents peptide binding. What is the mechanism by which the invariant chain is targeted to endosomes following class II association, an event which also frees it from retention in the ER? Both these properties, targeting and retention, may be mediated by interactions with proteins on the cytosolic face of intracellular membranes. These would be the ER membrane in the case of retention, and perhaps special- ized vesicles that bud from the tram Golgi for transport to endosomal vesicles. The identification of such proteins is a major goal for the future.

Acknowledgements

The work described from the authors’ laboratory was supported by grant no. A23081 from the National Institutes of Health.

References and recommended reading

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An elegant demonstration of the role of the cytoplasmic domain signals in the invariant chain in driving class II molecules to endosomes.

29. PETERS PJ, NEEFJES JJ, ORRXHOT V, PL~ECH HL, GEUZE HJ: . . Segregation of MHC Class I Molecules from MHC Class II

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ments. Cell 1990, 63707-716. The first demonstration of the ER and endosomal targeting signals present in the invariant chain cytoplasmic domain.

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Occurs in the Absence of the Invariant Chain. J Exp Med 1986, 164:1491&1504.

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Contains the unusual observation that the invariant chain can facilitate the transport of class 11 a- and P-subunits derived from different hap- lotypes which assemble in the ER, but are not normally transported to the cell surface.

42.

43.

SCHAIFF WT, HRUSKA KA, BONO C, SHUMAN S, SCHWARTZ BD: Invariant Chain Influences Post-translational Processing of HLA-DR Molecules. J Immunol 1991, 147X503*8. PETEWN M, MILIXR J: Invariant Chain Influences the Im- munological Recognition of MHC Class II Molecules. Na- ture 1990. 345:172-174.

P Cresswell, Howard Hughes Medical Institute, Section of Immunobiol- ogy, Yale University School of Medicine, 310 Cedar St., 410 FMB, New Haven, Connecticut 06510, USA

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Chemistry and functional role of the invariant chain