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Annu. Rev. Cell. Biol. 1990.6:403-431. Downloaded from www.annualreviews.org Access provided by University of New England - Australia on 08/13/15. For personal use only.

THE T CELL ANTIGEN RECEPTOR: INSIGHTS INTO ORGANELLE BIOLOGyl Richard D. Klausner, Jennifer Lippincott-Schwartz, and Juan S. Bonifacino

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892 KEY WORDS:

subunit assembly, protein trafficking, endoplasmic reticulum, Iyso­ somes, degradation

CONTENTS INTRODUCTION....... .......................................... ............................................................. STRUCTURE OF THE T CELL ANTIGEN

Subunits oj the T Cell Antigen Receptor . ....... .. .. ...... ................................................. Subunit Interactions... ........................... .............. . . . . ...................................... ............ Assembly oj the T Cell Antigen Receptor Complex ...... ...... ................ . ........ ....... .......

404 405 405 410 411

RELATIONSHIP BETWEEN ASSEMBLY AND INTRACELLULAR FATE OF THE T CELL ANTIGEN RECEPTOR..........................................................................................................

412

Getting to the Cell SurJace ....... ...................... ........... ............. ... ......... .... .......... ...... .. Targeting the TCR to Lysosomes: The Role oJ, ................... .............. ................... .. Partial Complexes that Fail to Reach the Golgi System ..... . .............. ... ........ ... ...... .... Non-Lysosomal Degradation ojNewly Synthesized Proteins ........ ... ...................... ... Selectivity of ER Degradation ........ ....... ...... ................ ......... ....... ................ ......... .... Structural Determinants oj ER Degradation ....... ........... .... . ....... .. .......... ...... ... .. ........ Regulating the Intracellular Transport oj the TCR During Thymic Development ......

413 415

418 421 422 425

CONCLUSION......... ........................................ ................................................................

427

I The

418

US Government has the right to retain a nonexclusive, royalty-free license in and to

any copyright covering this paper.

403

404

KLAUSNER, LIPPINCOTT-SCHWARTZ & BONIFACINO

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INTRODUCTION One of the major goals of eukaryotic cell biology is to understand the structure and function of the various membrane-bound organelles. The selective passage of molecules into and between these compartments under­ lies many of the critical functions of the cell. In no process is this more dramatically illustrated than in the expression of plasma membrane proteins. The life of an integral membrane protein begins by its synthesis on the cytoplasmic face of the rough endoplasmic reticulum (ER). During or soon after synthesis, the transmembrane topology of the protein is established in the ER. The protein is transported via vesicles from the ER to the Goigi system and eventually to the plasma membrane. From the time of synthesis, the protein is acted on by many cellular components that catalyze and ensure the maturation of the protein (Kornfeld & Kornfeld 1985; Rothman 1989). These components are involved in folding and post-translational modifications. It is clear that many of these modi­ fications, especially glycosylation and carbohydrate processing, occur in a defined, step-wise fashion through sequential organellar compartments. Thus many of these modifications are imposed in both a temporally and spatially defined fashion through the secretory pathway. Information accrued over the past decade has shown that many of these plasma membrane proteins are present in multimeric complexes. These complexes may be homo- or hetero-oligomers, and the complexes may be held together by either covalent or noncovalent interactions (see recent review by Hurtley & Helenius 1989). One of the largest membrane com­ plexes described to date is the T cell antigen receptor (TCR). This hetero­ oligomeric complex is composed of at least seven chains encoded by six different genes. It is a receptor found uniquely on T lymphocytes, and it is responsible for the ability of T cells to recognize and respond to specific antigens. Two problems. must be solved by the cell in order for it to express complex assemblies at the plasma membrane. First, the cell must suc­ cessfully assemble the complex. This may occur via spontaneous self­ assembly, or with the help of accessory proteins. Second, for proper func­ tion the cell must ensure that only correct, fully assembled complexes are expressed on the cell surface. While a correlation between the assembly state of components of oligomeric complexes and their intracellular fates has been observed for many systems, recent studies of the TCR suggest an extraordinary marriage of the biochemistry of protein assembly to the principles of sorting and transport of proteins through the secretory vacuolar system. Accordingly, the spatial fate of TCR componentf> appears to be intimately linked with their successful structural maturation. The cell

T CELL ANTIGEN RECEPTOR

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effectively edits out abnormal receptors or incomplete complexes from the final secretory pathway. This is accomplished by either retaining the proteins early in the secretory pathway, or targeting the proteins for rapid degradation. In this review we will focus on these cellular editing processes, relating the complexity of the T cell antigen receptor to its intracellular movement and ultimate fate in the cell.

STRUCTURE OF THE T CELL ANTIGEN RECEPTOR Subunits of the T Cell Antigen Receptor

Current data suggest that all T cell antigen receptors are composed of at least seven transmembrane chains (Figure I and Table I). All of these chains are relatively small (core polypeptide molecular weights range

L-----..J '-----1 ,'-__ -'

Zeta and Clonotypic zeta·related chains chains

Figure 1

CD3 chains

Subunit structure of the TCR complex. The scheme shows the minimal subunit

composition of the most commonly found type ofTeR complex and the membrane topology of the TCR chains. Some receptor complexes contain a clonotypic Ti-yb heterodimer instead of Ti-oc!J. Others contain disulfide-linked (17 or (-Fc y heterodimers instead of" homodimers.

406 Table I

KLAUSNER, LIPPINCOTT-SCHWARTZ & BONIFACINO

Characteristics of the murine TCR chains Charged amino acid residues in M, of the mature

N-linked

transmembrane

protein (reduced)

carbohydrate chains

domain

Ti-o:

40-44

4

Arg-Lys

Ti-fJ

40-44

4

Lys

Ti-l'

32-35

0-2

Lys

Ti-.5

45-46

3

Arg-Lys

TCR chains

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Clonotypic chains

CD3 chains CD3-y

21

I

Glu

CDH

26

3

Asp

CD3-B

25

0

Asp

TCR -(

16

0

Asp

TCR I] -

22

0

Asp

7

0

Asp

Zeta-related chains

Fc-y

Data were taken from Hedrick et al 1984; Chien et al 1984a,b; Saito et al 1984; Becker et al \985; Samelson et al 1985; van den Elsen et al 1985b; Krissansen et al 1987; Haser et al 1987; Gold et al 1987a; Bonyhadi et a1 1987; Weissman et a11988a; Baniyash et a11988; Blank et a11989; Cron et a11988; Raulet 1989; Jin et al 1990.

between 15 and 30K). They all possess N-termina1 1eader sequences and have a predicted topology with respect to the membrane that includes a single transmembrane domain with the amino terminus facing the outside of the cell. One intriguing feature of the transmembrane domains of each of the chains is that they possess one or two charged amino acid residues. Although there are different ways to classify the TCR subunits, one useful classification distinguishes clonotypic from invariant subunits. The clono­ typic subunits exist in the receptor as heterodimers. The majority of peripheral T cells express rx{3 disulfide-linked heterodimers as their clono­ typic receptor subunits. The remaining T cell antigen receptor possess two other clonotypic chains referred to as }' and 6 (reviewed by Brenner et al 1988; Raulet 1989). In this chapter we will discuss only r:x{3-containing T cell antigen reccptors. Thcsc chains are immunog1obin-like glycoproteins containing constant and variable regions (reviewed by Davis & Bjorkman 1988). Each T cell clone possesses a unique a{3 heterodimer. As with immunoglobulins, the tremendous array of sequences for a{3 heterodimers is achieved by genetic mechanisms including recombinatorial gene rearrangement and specific sequence diversification. Not surprisingly, the clonotypic heterodimer is entirely responsible for the ligand specificity of

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T CELL ANTIGEN RECEPTOR

407

the receptor. Both the a and {3 chains consist of core polypeptides of 2830K. Each has several N-linked glycosylation sites and the glycans linked to them raise the apparent molecular weight on SDS-PAGE of the mature IX or {3 subunits to 40-44K. They are disulfide-linked via a single cysteine pair. These chains are remarkable for their extremely short cytoplasmic tails of between 4 and 10 amino acids. The similarity between immu­ noglobulins and the extracellular domains of the 1X{3 subunits of the TCR has led to models in which these domains are folded into immunoglobulin­ like three-dimensional structures. Direct structural analysis of these domains, however, has not been achieved. The remaining subunits are invariant, i.e. they are identical in sequence for all T cell clones. It has long been assumed that these chains function in signal transduction. Only recently evidence supporting the role of the ( chain in signaling has been obtained (Sussman et al 1988a; Mercep et al 1989). In contrast to the a{3 heterodimers whose transmembrane domains possess one or two positively charged amino acids, all of the invariant chains possess a single negatively charged amino acid in their predicted transmembrane helices (van den Elsen 1984, 1985b; Krissansen et a1 1986, 1987; Haser et al 1987; Gold et al 1986, 1987a; Weissman et al 1988a,b; Jin et al 1990). The properties of the invariant subunits are best discussed if they are subdivided into two classes: CD3 and ( (Table I). CD3 was initially defined as a surface antigen present on mature human thymocytes and peripheral T cells and was identified as a result of the development of T-cell specific monoclonal antibodies (Reinherz et al 1979). Since CD3 was found before the antigen-binding subunits of the TCR were identified, its history led to some confusion and, for some time, obscured the fun­ damental subunit nature of all of these components. The earliest recog­ nition that the TCR was part of a complex was suggested by studies using human T cells that demonstrated an interaction between CD3 and the then newly discovered a{3 heterodimer (Reinherz et al 1982, 1983; Meuer et a1 1983; Weiss & Stobo 1984). CD3 is actually a complex of three different proteins, termed CD3-y, -b, and -6 (Borst et al 1983a,b, 1984). Genetic analysis has proven the close relationship of these three subunits. Each of these chains shows a high degree of sequence similarity to the others (van den Elsen et al 1984; Krissansen et al 1986; Gold et al 1986, 1987a). The genes encoding these three subunits are clustered in a small region of human chromosome 9 and mouse chromosome 11 (van den Elsen 1985a; Tunnacliffe et al 1987; Gold et a1 1987b; Clevers et al 1988). The genes for y and b lie in a head-to-head orientation within 1.5 kb of each other on the chromosome (Tunnacliffe et al 1987). The three genes most likely arose from an ancestral gene by a process of gene duplication.

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408

KLAUSNER, LIPPINCOTT-SCHWARTZ & BONIFACINO

Gamma and b are both glycoproteins. Their core molecular weights are approximately 16K. In the mouse, CD3-bhas a mature apparent molecular weight on SDS-PAGE of approximately 26K; while y migrates at approxi­ mately 21K (Samelson et al 1985; Oettgen et al 1986). The difference in migration is a result of the presence of three N-linked carbohydrate chains on b compared to one on y. In the human CD3 complex the electrophoretic mobilities of y and (j are reversed, as a result of a reversal in the number of N-linked glycans. Epsilon is not glycosylated and migrates on SDS­ PAGE under reducing conditions with an apparent molecular weight of approximately 25K (Samelson et al 1985; Oettgen et al 1986). In contrast to a{3, the mass of the polypeptide chains for each of these subunits is distributed approximately equally between extracellular and cytoplasmic domains. The extracellular domains have structural homology to immu­ noglobulin domains, and it is likely that all of them possess intrachain extracellular disulfide bonds (Gold et al 1987a). The, chain is not considered to be a CD3 component as it is genetically and structurally distinct from the CD3 complex (Weissman et aI1988a,b). In addition, whereas the CD3 components are always expressed together in T cells, the' chain is found in several cell types, including natural killer (NK) cells in the absence of expression of CD3 chains (Anderson et al 1989; Lanier et aI1989). In fact, it appears that ( can also exist as a subunit of a class of Fc receptors and, therefore, is not restricted to the TCR (Lanier et aI1989). Zeta is encoded by a gene located in a conserved linkage group of genes on chromosome I in both mouse and man (Weissman et al 1988b; Baniyash et al 1989). Zeta was first discovered as a disulfide­ linked homodimer of two 16K non-glycosylated peptides (Samelson et al 1985), and its topology with respect to the membrane is essentially the mirror image of a{3. Zeta contains approximately 8 amino acids in its extracellular domain, followed by a single transmembrane domain, and a long (113-115 amino acid) cytoplasmic tail (Weissman et al 1988a,b). Recent work suggests that, is a member of a larger family of genes that encodes receptor subunits. The first relevant suggestion came with the finding, initially in murine T cells, that , existed in two forms, both of which were part of the TCR complex (Baniyash et al 1988). While the predominant form of, in these cells is as a homodimer, approximately 10% of, is found as a heterodimer with a 22K non-glycosylated protein, which we have termed Yf (Baniyash et al 1988; Orloff et al 1989). Bio­ chemical characterization of Yf revealed that it does not represent a post­ translational modification of C. When the eDNA encoding C is transfected into either fibroblasts or, -deficient T cells, no Yf is produced (Weissman et

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a11989; Orloff et aI1989). In addition, I] does not appear to be glycosylated, sulfated, phosphorylated, or ubiquitinylated. Nonetheless, I] is clearly structurally related to (. Although this can be inferred from its dimer­ ization, direct evidence comes from the development of antibodies that can directly recognize both ( and I] (Orloff et al 1989). The latter were developed by synthesizing peptides corresponding to regions of the cyto­ plasmic tail of (. Groups of animals were immunized against these different peptides for the production of anti-( anti-peptide antibodies. All animals injected with two particular peptides developed antibodies that directly recognized I] (Orloff et al 1989). In contrast, antibodies raised against other regions of ( have, so far, never resulted in anti-I] antibodies. The recent cloning of a cDNA encoding the IJ chain has confirmed these observations by demonstrating that IJ derives from an alternatively spliced RNA product of the ( chain gene (Jin et al 1990). Zeta and I] are thus identical through amino acid 122 of the mature proteins, but have different carboxyl-terminal sequences (Jin et al 199 0). Our current model for the TCR complex con­ tains either a single (-( homodimer, or a single (-I] heterodimer. It is important to point out, however, that the exact stoichiometry of ( in each complex has not been definitively proven; moreover, we have not directly checked whether complexes containing the heterodimer also contain the homodimer. Definitive evidence for the existence of other (-related genes came from the analysis of what appeared to be an entirely separate multisubunit receptor complex. In establishing the structure of the high affinity Fc receptor for IgE, Kinet, Metzger & colleagues established the existence of three distinct subunits: IY. (responsible for IgE binding), f3 and y (Metzger et al 1986; Blank et al 1989). The cloning of the cDNA and gene encoding y revealed its close relationship to ( (Blank et al 1989; Ra et al 1989a,b). Fc-y is a transmembrane protein that exists in the IgE receptor as part of a homodimer disulfide-linked by a single extracellular bond. Like" it has a very short extracellular domain and a transmembrane helix, followed by a relatively long cytoplasmic domain. Sequence comparison revealed that one region of ( and Fc-y were highly similar. This region includes the extracellular and transmembrane domains and is encoded by a single exon (exon 2) in both genes. Both Fc-y and ( genes are localized to chromosome 1, and these genes are likely to have arisen by duplication. Fc-y contains five exons while ( contains eight (Baniyash et al 1989). Recent evidence suggests that both y and ( can interact with Fc receptors, and recently we have demonstrated that this family of proteins not only forms homodimers, but can also form "promiscuous" heterodimers (D. Orloff et aI, unpub­ lished observations). Thus in addition to (-I], we have observed (-Fc y and

4lO

KLAUSNER, LIPPINCOTT-SCHWARTZ & BONIFACINO

1] Fc y-dimers. The functional significance of these dimers is now being examined.

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Subunit Interactions

An important goal of receptor research in the immune system will be achieved with a detailed description of the structure of the TCR complex. Unfortunately, we are far from that goal at this point. The first step towards an overall picture of the structure of the TCR complex is to establish the relationship of the different subunits to each other. This has been approached by examining the interaction between subunits in T cells that synthesize only a subset of the components or in cells that have been transfected with combinations of cDNAs encoding TCR subunits. Results from these studies suggest that the three types of TCR complex components, i.e. the a{3 heterodimer, the CD3 complex, and (, can be viewed as individual structural clusters. Thus, when the a and {3 chains are expressed alone in fibroblasts, they readily dimerize into the appropriate disulfide-linked heterodimer in the absence of any other chains (Bonifacino et al 1988a). In addition, ( dimerizes in the absence of any other chains (Orloff et al 1989). Finally, the CD3 complex can be assembled in cells transfected with cDNAs encoding the y, band s subunits (Berkhout et al 1988). We have also found that CD3-b readily combines with CD3-s (Bonifacino et al 1988a). Likewise, CD3-y will combine with CD3-s (Boni­ facino et al 1988a). Either of these interactions independently results in structural alterations of the extracellular region of s demonstrated by the induction of two distinct antigenic epitopes as a result of assembly (Bonifacino et al 1989; N. Manolios, R. D. Klausner, unpublished obser­ vations). Additional work has suggested that the cytoplasmic tail of s is not required for assembly into the complex (Transy et al 1989) and that the cytoplasmic tail of bis not required for the assembly with s (T. Rutledge et al manuscript in preparation). Assembly of murine CD3-bwith murine (CD3-y has not been detected (N. Manolios, R. D. Klausner, unpublished observations). It appears that y and bwill only be part of the same complex in the presence of CD3-s. Thus the CD3 complex consists of a core of s to which both y and bare assembled. Transfection of a and {3 into the same cells that have been transfected with the CD3 complex encoding genes results in the assembly of a pentamer (N. Manolios, R. D. Klausner, unpublished observations). Which chains mediate the interaction between the clonotypic heterodimer and CD3? Current data in the murine system points to the interaction between rx{3 and several CD3 chains as connecting the clonotypic to the invariant chains (N. Manolios, R. D. Klausner, unpublished observations). A previous study addressed this question in

T CELL ANTIGEN RECEPTOR

411

the human system using covalent cross-linking reagents and provided convincing evidence that TCR-fJ could be specifically cross-linked to CD3y (Brenner et aI198S).

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Assembly of the T Cell Antigen Receptor Complex

As is becoming widely accepted for the assembly of other multicomponent membrane complexes, it now appears that the assembly of the TCR sub­ units takes place in the ER (Alarcon et al 1988; Bonifacino et al 1988b). To be more precise, the assembly takes place before the complex reaches the Golgi system. This is determined primarily by comparing the rate of assembly of newly synthesized components with their rate of carbohydrate processing, using the latter as a signature of having reached the Golgi system. Unfortunately, relatively little is known about the details of the assembly of the TCR complex. For example, it is not known whether there is a precisely defined order of assembly or whether different assembly pathways can all result in a fully assembled complex. The covalent dimer­ ization of" either with itself or with 1'/, occurs within minutes of synthesis (Orloff et al 1989). In contrast, the disulfide linkage of afJ is much slower with a half time of between 10 and 30 min, depending upon the cell examined. Although afJ can disulfide link to each other in the absence of any other chains (Bonifacino et al 1988a), it is clear that non-disulfide linked a and fJ chains can first assemble with the CD3 complex and subsequently become covalently linked (Alarcon et al 1988; Koning et al 1988). It has become increasingly clear over the last several years, that there is a class of proteins that assists in the folding and assembly of multimeric complexes. These proteins have been called polypeptide chain-binding proteins or chaperonins (Rothman, 1989; Hemmingsen et a1 1988; Gatenby & Ellis, this volume). Some may be used during the process of assembly of many complexes, while others may be dedicated to the assembly of specific structures. A characteristic of these proteins is that they associate with unassembled components and are not found in the final mature assembled complex. A candidate for a chaperonin for the TCR has been identified in both human and murine T cells. This protein has been given several names including T3-p28 or CD3-w in human T cells (Pettey et al 1987; Alarcon et al 1988) and TRAP in murine T cells (Bonifacino et al 1988b). The latter acronym stands for T cell Receptor Associated Protein. TRAP is a 26-28 kd non-glycosylated protein with a very basic pI (Bon­ ifacino et al 1988b). It is readily seen after metabolic pulse labeling and immunoprecipitation of TCR complex components. It is specifically co­ precipitated as a noncovalently linked component complexed with newly

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412

KLAUSNER, LIPPINCOTT-SCHWARTZ & BONIFACINO

synthesized CD3 chains. TRAP is not immunoprecipitated by antibodies directed against either, or the clonotypic heterodimer (Bonifacino et al 1988b). This has led to a model suggesting that the addition of af3 to the CD3 complex is accompanied by the release of TRAP (Alarcon et aI 1988). Using a variety of amino acids, TRAP can be metabolically labeled to a specific activity comparable to that of the newly synthesized CD3 chains with which it is associated. This suggests that there is not a large pool of TRAP within the ER to which the newly synthesized chains of CD3 bind. Indeed, studies of the fate of TRAP in T cells supports this conclusion. TRAP is seen associated with CD3 components from the earliest time of synthesis. The kinetics of association of TRAP with CD3 have not been established. TRAP remains associated with CD3 for approximately 10-20 min during which time thc level of association remains constant. Then TRAP disppears and can no longer be co-immunoprecipitated with the cohort of metabolically labeled CD3 chains. The dissociation of TRAP occurs before the complex reaches the Golgi system (Bonifacino et al 1988b). Recently we observed that TRAP is first cleaved in a pre-Golgi com­ partment to a 15-kd protein that remains associated with CD3 before it is lost (Antusch et al 199 0). A variety of maneuvers can inhibit the loss of TRAP including the addition of the fungal antimetabolite, brefeldin A, or of the proton ionophore, monensin, and lowering the temperature. As the temperature decreases from 37°C, the appearance of the cleaved form of TRAP slows down, and both the intact and cleaved protein slowly disap­ pear. At temperatures below 25°C, there is no cleavage of TRAP and no loss of TRAP from the complex. The function of TRAP remains unclear. TRAP appears to be specific for T cells since when non-T cells are trans­ fected with cDNAs encoding CD3 chains, no TRAP-like molecules are co-pr�cipitated (Berkhout et al 1988; Bonifacino et al 1989). Despite this, assembly of the TCR complex in non-T cells that have been made to express the TCR subunits has been observed (Berkhout et al 1988; Boni­ facino et aI 1989). There is still no evidence, however, that their assembly state is absolutely identical to that seen in T cells that contain TRAP. Until TRAP is isolated and its gene cloned, it will be difficult to assign a function to this intriguing protein.

RELATIONSHIP BETWEEN ASSEMBLY AND INTRACELLULAR FATE OF THE T CELL ANTIGEN RECEPTOR Once it was determined that the antigen receptor on the surface of T lymphocytes was a multicomponent complex, two sets of observations

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T CELL ANTIGEN RECEPTOR

413

indicated that only fully assembled complexes were present on the cell surface. By utilizing antibodies that recognized different subunits of the T cell receptor complex, it was shown that all of the components that could be radioiodinated on the surface of cells were part of assembled complexes (Samelson et al 1986). Thus externally labeled ()( and p chains could be quantitatively immunoprecipitated by antibodies against CD3 components and vice versa. Additionally, when antibodies directed against the CD3 complex were cross-linked with anti-immunoglobulin antibodies to induce internalization and down-regulation of CD3, there was a comparable internalization and down-regulation of ()(p (Meuer et al 1983). Similar studies performed for surface labeled ( were used to demonstrate that all ( is associated with the rest of the complex on the surface of the cell (Weiss­ man et al 1986). Analysis of variants and mutants of human T cells that fail to express the clonotypic chains on their surface always fail to express surface CD3 chains and vice versa (Weiss & Stobo 1984; Sussman et al 1988a,c; Schmitt-Verhulst et al 1987; Chen et al 1988; Bonifacino et al 1988a, 1989). In the absence of synthesis of one of the chains, none of the remaining chains was expressed on the cell surface, but the expression of the entire complex on the cell surface could be reconstituted by the reintroduction of the gene encoding the missing chain (Ohashi et a1 198 5; Saito et al 1987; Sussman et a1 1988b; Weissman et aI1989). Recognition that only fully assembled complexes are expressed on the cell surface led to the question of how this was accomplished by the cell. The most extensive studies on the biosynthesis, assembly and intracellular fate of the TCR complex have been carried out in murine T cells by utilizing, in particular, an antigen-specific T cell hybridoma termed 2B4. We base the following discussion on those findings, comparing and con­ trasting them to observations made in other T cell systems. Biosynthetic studies of the TCR complex have revealed that the fate of newly synthesized chains is determined by the extent of their assembly into either partial or complete receptor complexes (Minami et al 1987b; Lippincott-Schwartz et al 1988; Chen et al 1988; Bonifacino et al 1989). Four distinct fates have been identified, including (a) transport to the plasma membrane for fully assembled, heptameric complexes, ()(Py&( 2; (b) transport to and degradation within lysosomes for pentameric ()(py& complexes lacking (; (c) retention and longevity in the ER; and (d) rapid, pre-Golgi degradation. Fate (c) or (d) occurs for isolated subunits, or any partial complex lacking a chain other than ( or 1'/ (Figure 2). Getting to the Cell Surface

When 2B4 cells are metabolically labeled, the rates of synthesis of all of the chains except for (and 1'/ are within a factor of two of being equivalent.

414

KLAUSNER, LIPPINCOTT-SCHWARTZ & BONIFACINO Plasma Membrane

___________________

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D"ooooo, Trans-Goigi N�twork

(

.Trans

(

Goigi System

Medial Cis

) ) ) )

( (

...... 0egradation ER

C

....... Retention

)

(n. C

The T cell antigen receptor: insights into organelle biology.

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