Reduced Immunoglobulin A Transcytosis Associated withImmunoglobulin A Nephropathy and NasopharyngealCarcinoma*

Received for publication, August 24, 2011, and in revised form, November 3, 2011 Published, JBC Papers in Press, November 15, 2011, DOI 10.1074/jbc.M111.296731

Tao Su‡, Steven J. Chapin‡1, David M. Bryant‡2, Annette M. Shewan‡3, Kitty Young‡, and Keith E. Mostov‡§4

From the Departments of ‡Anatomy and §Biochemistry and Biophysics, University of California, San Francisco, California 94158

Background: The A580V human pIgR polymorphism is associated with IgA nephropathy and nasopharyngeal carcinoma.Results: A580V mutation reduces pIgR/pIgA transcytosis and seemingly pIgR cleavage and release from the apical surface.Conclusion: The A580V polymorphism regulates pIgR and IgA-pIgR complex transcytosis across cells.Significance:Defects in pIgR trafficking and processingmay underlie the pathogenesis of IgA nephropathy and nasopharyngealcarcinoma.

Polymeric IgA (pIgA) is transcytosed by the pIgA receptor(pIgR) across mucosal epithelial cells. After transcytosis to theapical surface, the extracellular, ligand-binding portion of thepIgR is proteolytically cleaved. A missense mutation in humanpIgR, A580V, is associated with IgA nephropathy and nasopha-ryngeal carcinoma. We report that this mutation reduces therate of transcytosis of pIgR and pIgA, and seemingly the rate ofpIgR cleavage. We propose that the defects in pIgR traffickingcaused by theA580Vmutationmayunderlie the pathogenesis ofboth diseases.

The polymeric immunoglobulin receptor (pIgR)5 is a single-spanning transmembrane protein expressed onmany epithelialcells lining mucosal surfaces (1–3). At the basolateral (BL) cellsurface, the pIgR binds its ligand, polymeric IgA (pIgA). ThepIgA can in turn be bound to its antigen. The pIgR-pIgA com-plex is endocytosed and transcytosed through a series of endo-cytic vesicles to the apical (AP) surface. There, the extracellular,ligand binding domain of pIgR is proteolytically cleaved andreleased together with the pIgA into external secretions. Thiscleaved fragment of pIgR is termed secretory component (SC).A missense mutation (pIgR-A580V) in the extracellular

region of human pIgR is associated with increased risk of IgAnephropathy (IgAN) in Japan (4). IgAN is the main cause ofprimary glomerulonephritis worldwide, especially in east Asia;20–40% of patients progress to end stage renal failure (5). The

pIgR-A580V mutation has also been associated in two studieswith increased risk of nasopharyngeal carcinoma (NPC) inThaiand southern Chinese populations, where NPC is a leadingformof cancer (6–8). This result is intriguing, because Epstein-Barr virus (EBV), the causative agent of NPC, can enter epithe-lial cells via binding to the pIgR of pIgA antibodies directedagainst EBV (9, 10).

EXPERIMENTAL PROCEDURES

Plasmids, Viral Production and Transduction, and CellCulture—Human pIgR in pcDNA3.1 was kindly provided by C.Kaetzel (University of Kentucky). The A580V point mutationwasmade byQuikChangemutagenesis (Stratagene). pIgR (WTand A580V) coding sequence was transferred to pLZRS-MS/IRES-GFP retroviral vector (A. Reynolds, Vanderbilt Univer-sity), giving expression of hpIgR and GFP under IRES control.Viral production and transduction were performed asdescribed (11), with some modifications. pLZRS vectors weretransfected into 293-GPG packaging cells (O. Weiner, Univer-sity of California San Francisco). The following day, freshmedium was added, and viral supernatants collected 3 daysafter transfection. For retrovirus transduction, subconfluentMadin-Darby canine kidney (MDCK) cells 16–24 h after plat-ing were incubated with virus-containing supernatants for 48 hat 37 °C. Stable lines weremade using two complementary pro-cedures: (i) direct transfection of pcDNA3.1-pIgR followed byantibiotic-mediated selection (0.5 mg/ml G418 for 2–3 weeks)and screening for hpIgR-positive clones, or (ii) viral transduc-tion (see below) using pLZRS-MS/IRES-GFP-pIgR (WT andA580V) followed by FACS to enrich for pools of GFP-express-ing cells. All assays were verified using cell lines made by bothmethods, ensuring differences noted were due to the A580VpIgR mutation and not clonal variation. pIgR-expressingMDCK cells were grown as described (11, 12), on 12 or 24 mmpolycarbonate Transwell filters (Corning) for 3–4 days for allexperiments.pIgR Transcytosis Assay by BL Biotinylation—Biotinylation

was performed at 17 °C (11, 12). Cells (on 12-mm filters) werewashed three times with Hanks’ balanced saline solution(HBSS) containing 20mMHEPES and biotinylated basolaterally

* This work was supported, in whole or in part, by National Institutes of HealthGrant R01AI25144 (to K. E. M.).

1 Present address: Perseid Therapeutics, 515 Galveston Dr., Redwood City, CA94063.

2 Supported by a Susan G. Komen Foundation postdoctoral fellowship.3 Supported by a National Health and Medical Research Council C. J. Martin

fellowship. Present address: School of Chemistry and Molecular Biosci-ences, the University of Queensland, St. Lucia, Queensland 4072, Australia.

4 To whom correspondence should be addressed: UCSF GH N212B, 600 16thSt., San Francisco, CA 94158-2517. Fax: 415-514-0169; E-mail: keith.mostov@ucsf.edu.

5 The abbreviations used are: pIgR, polymeric immunoglobulin receptor; AP,apical; BL, basolateral; HBSS, Hanks’ balanced saline solution; IgAN, IgAnephropathy; MDCK, Madin-Darby canine kidney; MEM, minimum essen-tial medium; NPC, nasopharyngeal carcinoma; pIgA, polymeric IgA; SC,secretory component.

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 286, NO. 52, pp. 44921–44925, December 30, 2011© 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

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with 0.5 mg/ml LC-NHS-biotin (Pierce) in HBSS for 30 min;500 �l of MEM with 0.6% BSA (w/v), 20 mM HEPES, 100units/ml penicillin, and 100 �g/ml streptomycin (MEM/BSA/HEPES) was added to the AP side. Cells were washed withMEM/BSA/HEPES buffer three times for 20 min at 17 °C toremove excess biotin. Transwells were transferred to 150-�ldrops ofMEM/BSA/HEPES�pIgA (0.3mg/ml) in a humid boxfor 10min at 17 °C (with 250�l ofMEM/BSA/HEPESon theAPside). Cells were then transferred to a 37 °Cwater bath. Another250 �l of 37 °C MEM/BSA/HEPES buffer was added to the APchamber of filters to change the temperature to 37 °C. After thechase, 350 �l of coldMEMwas added to the BL side, and filterswere placed onto an ice-cold metal plate. AP medium was col-lected, and cells were lysed in 500 �l of 0.5% SDS (w/v) lysisbuffer containing 100 mM NaCl, 50 mM triethanolamine HCl,pH 8.6, 5 mM EDTA HCl, pH 8.0, 0.2% Trasylol (v/v), 0.02%NaN3 (w/v). Sampleswere boiled for 10min and vortexed for 15min at room temperature. Samples were then precleared withSepharose CL2B beads, and 500 �l 2.5% (v/v) Triton dilutionbuffer containing 100 mM NaCl, 100 mM triethanolamine HCl,pH 8.6, 5 mM EDTA HCl, pH 8.0, 1.0% Trasylol (v/v), 0.02%NaN3 (w/v) was added before immunoprecipitation with 30 �lof protein G beads (and 1 �g/sample of rabbit anti-human SCantibody (Dako and Santa Cruz Biotechnology) overnight at4 °C. Immunoprecipitated samples were analyzed by gel elec-trophoresis and Western blotting using IRD800-streptavidin.Protein bands (Pierce) were visualized by LI-COR BiosciencesOdyssey NIR Imager scanner.pIgA Transcytosis by ELISA Analysis—Cells on a 12-mm fil-

ter were treated with 100 �g/ml biotinylated pIgA (biotinyla-tion procedure was based on the manufacturer’s instructions(Pierce) from the BL surface at 37 °C for 20, 40, and 80min (11).AP media were collected, and cells were lysed in 0.5% NonidetP-40 (v/v) lysis buffer containing 125 mMNaCl, 20 mMHEPES,4 mM MgCl2, and protease inhibitors mixture. The amount ofbiotinylated pIgA, collected from either the AP medium aftertranscytosis or remaining in cells, was measured by ELISA. Inbrief, streptavidin-coated 96-well plates were blocked with 2%BSA in PBS. Samples collected at indicated time points werediluted in 2% BSA/PBS/T (0.5% Tween 20 v/v) and preincu-bated at 37 °C for 1 h.Wells were first treated with mouse anti-biotin antibody (1:5,000) (Jackson ImmunoResearch) for 2 h at37 °C and then with HRP-conjugated rabbit anti-mouse IgG(1:10,000) (Jackson ImmunoResearch) for 1 h at 37 °C. 3,3�,5,5�-Tetramentylbenzidine substrate (Pierce) was used for detec-tion. Plates were scanned by EMax precision microplate reader(Molecular Devices), and data were analyzed by Softmax soft-ware and exported to Excel for statistical analysis.pIgA-pIgR AP Endocytosis by pIgA Binding—Cells grown on

12-mm Transwells were washed twice with cold MEM andincubated with biotinylated pIgA at 4 °C on ice for 2 h. Cellswerewashed six timeswith coldMEM/BSA/HEPES buffer for 5min each cycle. Filters were placed in a prewarmed dish withmedium, and 150 �l/filter prewarmed MEM/BSA/HEPESbuffer was added to the AP chamber of filters at 37 °C for 2, 5,10, and 30 min. Media samples were collected. Monolayerswere treated with trypsin- tosylphenylalanyl chloromethylketone (100 �g/ml) (Worthington Biochemical) apically and

with soybean trypsin inhibitor at the BL side at 4 °C for 1 h.Trypsinwas thenquenchedwith 10%horse serum inMEM, andcells were lysed in 0.5% Nonidet P-40 lysis buffer. Control cellsremained on ice without protease before lysis. All samples wereanalyzed by gel electrophoresis and immunoblotting for pIgRand biotinylated pIgA.pIgR AP Cleavage by AP Biotinylation—Cells grown on

24-mm Transwells were washed with ice-cold HBSS and bioti-nylatedwith 0.5mg/ml sulfo-NHS-LC-biotin inHBSS twice for15 min at 4 °C. Cells were washed with ice-cold MEM/BSA/HEPES buffer five times for 30 min. To start cleavage, pre-warmed MEM/BSA/HEPES buffer was added to the AP cham-ber, and cells were incubated for 5 min in a water bath at 37 °C.At the completion of each time point, corresponding filterswere transferred to a dish with medium at 4 °C on ice, andmedia samples were collected from the AP chamber. Monolay-ers were washed and lysed in 0.5% Nonidet P-40 lysis buffer at4 °C on ice. Cleaved SC and uncleaved endocytosed pIgRs weredetected by immunoprecipitation of pIgR using rabbit anti-hu-man pIgR, then immunoblotted for biotinylated SC and pIgRwithmouse anti-biotin antibodies (LI-COROdyssey). Cleavagelevels of pIgR were calculated as the fraction of AP media SC,expressed as a percentage of the total pIgR levels (AP SC �intracellular pIgR).Statistics—Data are expressed as mean� S.E. Student’s t test

was utilized to compare differences between wild-type andmutant cells. p and n values are presented in the figure legends.

RESULTS

To investigate how the pIgR-A580V mutation can underlieboth IgAN and NPC, we expressed wild-type human pIgR(pIgR-WT) and pIgR-A580V in polarized MDCK cells, whichhave been used extensively for studies of pIgR trafficking (13).Both pIgR-WT and pIgR-A580V were uniformly expressed atsimilar levels (Fig. 1).We measured transcytosis of pIgR by biotinylating it at the

BL surface and quantitating the subsequent release of biotin-SCinto the APmedium in the absence or presence of pIgA. AP SCrelease was reduced from 49.81� 1.47% (pIgR-WT) to 37.84�3.79% (pIgR-A580V), p� 0.008 in the absence of pIgA (Fig. 2A,top).Binding of pIgA to the pIgR is known to increase the rate of

transcytosis of the pIgR. We therefore determined the effect ofthemutation onAP SC release in the presence of pIgA added tothe BL medium. Under this condition, AP SC release was alsodecreased by the mutation, i.e. 54.6 � 1.29% (pIgR-WT) and

FIGURE 1. pIgR-WT and pIgR-A580V expression in MDCK cells. A, similarexpression level of pIgR is shown in pIgR-WT and pIgR-A580V cells by immu-nofluorescent (IF) staining. B, immunoblot (IB) shows duplicate pIgR-WT- andpIgR-A580V-expressing MDCK samples, with actin as a loading control, show-ing equivalent WT and A580V expression. Cropped boxes represent differentbands from the same gel and exposure.

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46.32 � 2.79% (pIgR-A580V), p � 0.015 (Fig. 2A, top). Thesmall amount of SC released into the BL medium was not sig-nificantly changed (Fig. 2A, middle), and similarly the amountof pIgR remaining associatedwith the cells was not significantlyaltered (Fig. 2A, bottom).Next, we followed the transcytosis of the ligand, biotinylated

pIgA, which was exposed to the cells via the BL medium. APmedium was collected at several time points and transcytosedpIgA quantitated. Transcytosis was significantly decreased inpIgR-A580V cells at 40 min (22.69 � 2.14% (WT) versus13.45 � 1.47% (A580V), p � 0.002) and 80 min (27.71 � 2.15%(WT) versus 21.85� 2.01% (A580V),p� 0.05) (Fig. 2B). A smallincrease in transcytosed pIgA occurred in pIgR-A580V cells at20min, although the total amount of transcytosis at this earliesttime point was very small. Taken together, these data revealdecreased overall IgA-transcytosis in cells expressingpIgR-A580V.When the pIgR reaches the AP surface, it is not instanta-

neously cleaved to SC. Some uncleaved pIgR can bind pIgA atthe AP surface, and the complex can then be endocytosed. Tomeasure AP endocytosis, we bound pIgA to pIgR at the APsurface at 4 °C and then warmed cells to 37 °C for various timesbefore cooling back to 4 °C. Internalized pIgA was then meas-ured by acquisition of protease resistance. pIgA internalizationwas significantly increased in pIgR-A580V-expressing MDCKcells compared with pIgR-WT-expressing cells (Fig. 3). Theendocytosis of WT versus mutant, respectively, was 10.84 �0.72% versus 15.2 � 1.05% at 5 min, p � 0.014; 27.13 � 3.13%versus 41.78 � 3.82% at 10 min, p � 0.015; and 38.93 � 3.18%versus 64.13 � 5.61% at 30 min, p � 0.002.

The N-terminal, extracellular region of pIgR consists of fiveimmunoglobulin-like domains, which become SC after proteo-lytic cleavage. This is connected by a stalk region to the singlemembrane-spanning segment of pIgR. The exact site(s) of thecleavage that converts pIgR to SC has not been definitivelydetermined (14, 15). TheAla-580mutation is in the stalk regionof pIgR and close to the likely cleavage site(s). It is possible thatthe pIgR-580V mutation decreases the rate of cleavage of pIgRat theAP surface. Ourmeasurement of pIgR transcytosis scoresrelease of SC into the APmedium, and so a decrease in cleavagewould decrease the apparent rate of transcytosis. The sameholds true for measurement of transcytosis of pIgA bound tothe pIgR. Furthermore, decreased cleavage could increase theamount of pIgR that enters the AP endocytic pathway ratherthan undergoing cleavage and thereby increase the apparentrate of endocytosis.To measure pIgR cleavage directly, we biotinylated pIgR at

the AP surface at 4 °C and then warmed the cells to 37 °C for 5min and quantitated the release of biotinylated SC. Indeed, therate of cleavage of pIgR to SCwas decreased by the pIgR-A580Vmutation. Cleavage of WT versus A580V, respectively, was24.03 � 0.94% versus 17.26 � 0.61%, p � 0.03 (Fig. 4). Thissuggests that the reduction in pIgR-A580V transcytosis is likelydue to reduced cleavage (13, 16, 17).

DISCUSSION

The pIgR has been studied extensively as a model for mem-brane trafficking and transcytosis in polarized epithelial cells.Its 103-residue cytoplasmic domain contains sorting signals forBL delivery, endocytosis, avoidance of degradation, and tran-scytosis (13, 16). The pIgR is also a signaling receptor in thatbinding of the pIgA ligand to the pIgR leads to activation of asignaling network involving the Src family kinase Yes, EGFR,ERK, FIP5, rab3b, retromer, phospholipase C�1, and increasedintracellular free calcium (2, 11). All of these processes involvetheC-terminal cytoplasmic domain of the pIgR. In contrast, thepIgR-A580V mutation is located in the extracellular region ofthe pIgR. In particular, this mutation is in the membrane prox-imal “stalk” region of the pIgR where proteolytic cleavage of SCoccurs. Indeed, themutation likely reduces this cleavage, whichprobably accounts for the observed decreased rates of transcy-tosis of pIgR and pIgA, as well as the increased AP endocytosisof pIgA.Our data do not exclude the possibility that the mutation

might instead alter the conformation of the pIgR in a way thatincreases AP endocytosis. As cleavage probably occurs at theAP surface, this increased endocytosis could cause a decrease inthe apparent rate of cleavage of the pIgR, thereby accountingfor all of our data.However, given the proximity of themutationto the cleavage site on the pIgR,we tend to favor the explanationthat the mutation directly reduces the rate of cleavage.IgAN and NPC are both complex, poorly understood dis-

eases. Many genetic and environmental risk factors are likely tobe involved and may account for the different outcomes (IgANversus NPC) in different populations. IgAN is characterized bymesangial deposits of IgA (mainly polymeric), often complexedwith antigen. Several loci have been identified with IgAN in agenome-wide association study (18). Another factor is altered

FIGURE 2. A580V mutation in human pIgR decreases pIgR/pIgA transcy-tosis in pIgR-expressing MDCK cells. A, pIgR/pIgA transcytosis was signifi-cantly decreased in pIgR-A580V-expressing cells, compared with pIgR-WT.Cells were basolaterally labeled with biotin at 17 °C for 30 min and washed at17 °C for 30 min. Cells were then chased with MEM/BSA at 37 °C for 60 min.Top, apically released SC (Ap-SC) is expressed as a percentage of total labeledpIgR in all fractions (i.e. SC in AP and BL media, and pIgR). Middle, basolaterallyreleased SC (BL-SC) is expressed as a percentage of total labeled pIgR in allfractions. Bottom, pIgR remaining in the cells is expressed as a percentage oftotal pIgR in all fractions. More AP-SC is seen in the pIgR-WT-expressing cellsthan for pIgR-A580V (n � 12). B, transcytosis of biotinylated pIgA was alsosignificantly decreased in pIgR-A580V-expressing cells compared withpIgR-WT after 40 and 80 min of transcytosis (n � 14).

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galactosylation of IgA1 (5). IgAN is likely a heterogeneousgroup of diseases, and pIgR-A580V may play a role only inselect populations, such as in Japan. We have shown that thepIgRA580Vmutation results in a decrease inAP SC release andsuggest that this is an additional factor contributing to bothdiseases. IgAN often follows mucosal infections, which causeincreased production of pIgA and pIgA-antigen complexes.Ordinarily, such pIgA-antigen complexes are efficientlyexcreted into mucosal secretions by pIgR (1). The reduced effi-ciency of transcytosis by pIgR-A580V could lead to buildup ofpIgA-antigen complexes, which would then be filtered out inthe kidney, resulting in IgAN (20). Although the effect of pIgR-A580V on transcytosis is modest (but statistically significant),this could be sufficient to account for a slow accumulation ofpIgA-antigen complexes, consistent with the multiyear timecourse of IgAN.

EBV is associated with infection and cancer in lymphocytes,e.g. Burkitt lymphoma, as well as NPC, an epithelial carcinoma(19). Complexes of pIgA bound to a surface protein of EBV areefficiently transcytosed across pIgR-expressing hepatocytesand polarized MDCK cells without causing EBV infection (9).However, nonpolarized pIgR-expressing HT29 human coloncarcinoma cells are infected by EBV, which enters the cells viapIgA-EBV complexes bound to pIgR. We suggest that thereduced efficiency of transcytosis of EBV by pIgR-A580V couldlead to infection, even in otherwise well polarized epithelialcells. Oncogenic transformation of one cell by EBVmay be suf-ficient to result in NPC. It is thus possible that even a slightincrease in the rate of infection of epithelial cells expressing themutant pIgR could lead to clinical NPC. Therefore, the modestdecrease in transcytosis caused by pIgR-A580V could be suffi-cient to account for the association of this mutation with NPC.Our results provide a unified model of how a slowing in

cleavage of pIgR by a missense mutation and the resultantdecreased transcytosis of pIgA may contribute to two distinctdiseases, IgAN and NPC, in vulnerable populations. This pro-vides potentially important clues in both understanding thepathogenesis of these diseases and perhaps how they might bebetter diagnosed, prevented, or treated.

Acknowledgments—We thank members of our laboratory for discus-sions. We thank C. Kaetzel for human pIgR cDNA.

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FIGURE 3. A580V mutation in human pIgR increases pIgA endocytosis in pIgR-expressing MDCK cells. A, filter-grown pIgR-WT- and pIgR-A580V-express-ing cells were treated apically with biotinylated pIgA at 4 °C. Cells were warmed to 37 °C for the indicated period to allow pIgR-pIgA internalization. Finally, cellswere cooled to 4 °C, and internalized pIgA levels were determined by resistance to exogenous protease addition. AP endocytosis is expressed as a percentageof total labeled pIgA. AP pIgA endocytosis rates were increased significantly in plgR-A580V-expressing cells compared with plgR-WT from 5 to 30 min (n � 4at 5 min, n � 6 at 10 and 30 min). B, representative Western blotting (IB) image from A. Samples with equal amount of protein were blotted for biotinylated pIgAshown as pIgA-HC (heavy chain) and pIgA-LC (light chain). Cropped boxes represent different bands from the same gel and exposure.

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E. MostovAnnette M. Shewan, Kitty Young and Keith Tao Su, Steven J. Chapin, David M. Bryant,  CarcinomaNephropathy and NasopharyngealAssociated with Immunoglobulin A Reduced Immunoglobulin A TranscytosisCell Biology:

doi: 10.1074/jbc.M111.296731 originally published online November 15, 20112011, 286:44921-44925.J. Biol. Chem. 

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