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A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion

Nature Cell Biology volume 26, pages 1077–1092 (2024)Cite this article

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A Publisher Correction to this article was published on 24 July 2024

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Abstract

Cargo translocation across membranes is a crucial aspect of secretion. In conventional secretion signal peptide-equipped proteins enter the endoplasmic reticulum (ER), whereas a subset of cargo lacking signal peptides translocate into the ER–Golgi intermediate compartment (ERGIC) in a process called unconventional protein secretion (UcPS). The regulatory events at the ERGIC in UcPS are unclear. Here we reveal the involvement of ERGIC-localized small GTPases, Rab1 (Rab1A and Rab1B) and Rab2A, in regulating UcPS cargo transport via TMED10 on the ERGIC. Rab1 enhances TMED10 translocator activity, promoting cargo translocation into the ERGIC, whereas Rab2A, in collaboration with KIF5B, regulates ERGIC compartmentalization, establishing a UcPS-specific compartment. This study highlights the pivotal role of ERGIC-localized Rabs in governing cargo translocation and specifying the ERGIC’s function in UcPS.

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Fig. 1: Rab1A, Rab1B and Rab2A regulate IL-1β secretion.
Fig. 2: The functions of Rab1 or Rab2A and TMED10 in IL-1β secretion are interdependent.
Fig. 3: Rab1A and Rab1B facilitate the entry of IL-1β into the ERGIC.
Fig. 4: Rab1A and Rab1B increase TMED10 oligomerization and promote its interaction with IL-1β.
Fig. 5: ERGIC positive for TMED10 is different from conventional ERGIC marked by ERGIC53.
Fig. 6: Rab2 regulates ERGIC compartmentalization positive for TMED10.
Fig. 7: KIF5B is required for the Rab2A-regulated ERGIC compartmentalization.

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Data availability

All data are available in the main text and the supplementary materials. For more information and requests for reagents, please directly contact the corresponding authors. Plasmids and cell lines in this study are available on request. If there is a potential commercial application, we may require a payment and/or a complete material transfer agreement. Source data are provided with this paper.

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Acknowledgements

The work was funded by National Natural Science Foundation of China (grant numbers 92254302, 32130023 and 32225013 to L.G.; and 32370728 to M.Z.), Ministry of Science and Technology of the People’s Republic of China (grant numbers 2021YFA0804802 and 2019YFA0508602 to L.G.) and Tsinghua University Dushi Program (M.Z.), and supported by the Vanke Special Fund for Public Health and Health Discipline Development, Tsinghua University (grant numbers 2022Z82WKJ009 to L.G. and M.Z.).

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  1. These authors contributed equally: Yuxin Sun, Xuan Tao, Yaping Han.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Tsinghua University–Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China

    Yuxin Sun, Yaping Han, Haodong Wang & Liang Ge

  2. State Key Laboratory of Membrane Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China

    Xuan Tao, Pei Chang & Min Zhang

  3. Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, China

    Xubo Lin

  4. Department of Biochemistry and Department of Cardiology of Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Rui Tian & Qiming Sun

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  1. Yuxin Sun
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Contributions

L.G., M.Z., Y.S. and X.T. conceived the experiments. L.G. and M.Z. supervised the project. Y.S., Y.H., L.G. and M.Z. wrote the manuscript. Y.S. and X.T. carried out the cell biology and biochemistry experiments. H.W. assisted with the in vitro translocation assay. P.C. assisted with the data processing of CLEM. X.L. performed the molecular dynamic simulation assay. R.T. and Q.S. provided the series of Rab plasmids.

Corresponding authors

Correspondence to Liang Ge or Min Zhang.

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Nature Cell Biology thanks Anbing Shi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Rab1A, Rab1B and Rab2A can regulate UcPS.

a, Immunofluorescence of HEK293T cells expressing GFP-ERGIC53 and TMED10-V5 with anti-Rab1A/Rab1B/Rab2A or anti-V5 antibody. Scale bar, 3 μm. b–d, IL-1β secretion in HEK293T cells transfected with mIL-1β-FLAG and GFP-tagged Rab1A (b)/Rab1B (c)/Rab2A (d) with different doses of plasmids for expression. e, IL-1β secretion in HEK293T cells co-transfected with mIL-1β-FLAG and FUGW/V5-Rab1A/1B/2A plasmids. f–h, IL-1β secretion in HEK293T cells co-transfected with mature (m) and precursor (p) IL-1β as well as GFP/GFP-Rab1A (f)/Rab1B (g)/ Rab2A (h) plasmids. *, Non-specific band. i, IL-1β secretion in HEK293T cells transfected with mIL-1β-FLAG and GFP-tagged Rab1A /Rab1B with V5-tagged Rab1B /Rab2A. Diagram showing the quantification of IL-1β secretion (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments, ns: no significant difference). e–i, R1A, Rab1A; R1B, Rab1B; R2A, Rab2A. j, The expression of Rab1A/1B in HEK293T cells transfected with control shRNA (sh Ctr) or shRNA against Rab1A and Rab1B (sh Rab1A+1B) and Rab2A/2B in HEK293T cells transfected with control shRNA (sh Ctr) or shRNA against Rab2A and Rab2B (sh Rab2A+2B). k–r, IL-1β secretion in sh Ctr and sh Rab1A+1B /sh Rab2A+2B transfected with GFP or other Rabs. The data are representative of three independent experiments. Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

Source data

Extended Data Fig. 2 Rab1A, Rab1B and Rab2A regulate the secretion of a series of UcPS cargoes.

a–c, ssGFP secretion in HEK293T cells co-transfected with ssGFP and BFP/BFP-Rab1A (a)/1B (b)/2A (c) plasmids with or without BFA treatment (0.5 ng/μl). *, Non-specific band. d,e, IL-6 (d)/IL-10 (e) secretion in HEK293T cells transfected with control siRNA (si Ctr) or siRNAs against Rab1A/1B/2A. f–h, ssGFP (f)/IL-6 (g)/IL-10 (h) secretion in HEK293T cells transfected with control siRNA (si Ctr) or siRNAs against Rab1A and Rab1B. i–k, Secretion of IL-18 in HEK293T cells co-transfected with IL-18-FLAG and GFP/GFP-Rab1A (i)/1B (j)/2A (k) plasmids. l–n, Secretion of IL-33 in HEK293T cells co-transfected with IL-33-FLAG and GFP/GFP-Rab1A (l)/1B (m)/2A (n) plasmids. o–q, Secretion of IL-36α in HEK293T cells co-transfected with IL-36α-FLAG and GFP/GFP-Rab1A (o)/1B (p)/2A (q) plasmids. *, Degradation band. r–t, Secretion of HSPB5-FLAG in HEK293T cells co-transfected with HSPB5-FLAG and GFP/GFP-Rab1A (r)/1B (s)/2A (t) plasmids. u–w, Secretion of Galectin-3 in HEK293T cells co-transfected with Galectin-3-FLAG and GFP/GFP-Rab1A (u)/1B (v)/2A (w) plasmids. a–w, The data are representatives of three independent experiments. R1A, Rab1A; R1B, Rab1B; R2A, Rab2A. Source unprocessed blots are available in source data.

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Extended Data Fig. 3 The function of Rab1A, Rab1B and Rab2A in IL-1β secretion depends on GTP binding and geranylgeranyl modification.

a–c, IL-1β secretion in HEK293T cells expressing GFP-Rab1A (a)/Rab1B (b)/Rab2A (c) with or without co-transfection of HA-TBC1D20. The quantification of IL-1β secretion (mean ± SD) was shown in the right. P values are indicated (two-tailed t test, n=3 experiments). L, low exposure; H, high exposure. d,e, IL-1β secretion in HEK293T cells transfected with control siRNA or siRNA against mTrs130 followed by expressing GFP/GFP-Rab1A (d)/Rab1B (e). The quantification of IL-1β secretion (mean ± SD) was shown in the right. P values are indicated (two-tailed t test, n=3 experiments). f, IL-1β secretion in HEK293T cells transfected with control siRNA or siRNA against Clec16A followed by expressing GFP/GFP–Rab2A. The quantification of IL-1β secretion (mean ± SD) was shown in the right. P values are indicated (two-tailed t test, n=3 experiments). g, mIL-1β secretion in THP-1 cells with FUGW (empty) or HA-TBC1D20 expressed. *, Non-specific band. h, Galectin-3 secretion in SW620 cells with FUGW (empty) or HA-TBC1D20 expressed. *, Non-specific band. i–k, Galectin-3 secretion in SW620 cells with FUGW (empty) and Rab1A S25N (i)/Rab1B S22N (j)/Rab2A S20N (k). l, IL-1β secretion in HEK293T cells co-transfected with Rab1A/1B/2A or CC/SS mutants. g–l, The data are representatives of three independent experiments. m, The expression of GFP-Rab1A/1B/2A compared with endogenous Rab1A/1B/2A in HeLa cells. The ratio of GFP-Rabs to endogenous Rabs is shown in the right. g–m, R1A, Rab1A; R1B, Rab1B; R2A, Rab2A. n, Immunofluorescence of HeLa cells with expression of mcherry-ERGIC53 and GFP-Rab1A/1B/2A or CC/SS mutants. Scale bar, 5 μm. Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

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Extended Data Fig. 4 The pivotal role of Rab1 and Rab2A in TMED10-mediated UcPS.

a–c, IL-1β secretion in HEK293T cells transfected with control siRNA (si Ctr) or siRNA against TMED10 (si TM10) followed by expressing mIL-1β-FLAG and GFP/GFP-Rab1A (a)/Rab1B (b)/Rab2A (c). The quantification of IL-1β secretion is shown below (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments). L, low exposure; H, high exposure. d–f, IL-1β secretion in HEK293T cells transfected with GFP-Rab1A/1B/2A alone, TMED10-V5 alone or GFP-Rab1A/1B/2A and TMED10-V5. g–i, Co-IP analysis of HEK293T cells expressing TMED10-V5 with GFP/GFP-Rab1A (g)/1B (h)/2A (i) and their mutants. d–i, The data are representatives of three independent experiments. a–i, R1A, Rab1A; R1B, Rab1B; R2A, Rab2A. Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

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Extended Data Fig. 5 The function of mutants of Rab1 and Rab2A in UcPS.

a, Co-IP analysis of HEK293T cells expressing TMED10-V5 with GFP/ GFP-Rab1A/T75D/ GFP-Rab1B/T72D. b, Co-IP analysis of HEK293T cells expressing TMED10-V5 with GFP/GFP–Rab2A/Y3D. c–h, Time evolution curves (c–e) and statistical averages (f–h, mean ± SD) for the nonbonded interaction energy between Rab and TMED10-CT in the wild-type (grey) and mutant (red) MD simulation systems of Rab1A (c,f), Rab1B (d,g), and Rab2A (e,h). i, Immunofluorescence of HeLa cells with expression of mcherry-ERGIC53, TMED10-V5 and GFP-Rabs. Immunofluorescence was examined with anti-V5 antibody. Scale bar, 5 μm. j,k, HeLa cells were transfected with control siRNA (si Ctr) or siRNAs against Rab1A/1B/2A followed by coexpressing mcherry-ERGIC53, TMED10-V5 and Rabs/Rab mutants. Immunofluorescence was examined with anti-V5 antibody. Scale bar, 5 μm. l,m, IL-1β secretion in HEK293T cells transfected with mIL-1β-FLAG and GFP-tagged Rab1A /Rab1B /Rab2A /their mutants. a,b,l,m, R1A, Rab1A; R1B, Rab1B; R2A, Rab2A. Source numerical data and unprocessed blots are available in Source data.

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Extended Data Fig. 6 Rab1 can facilitate IL-1β enter into the TMED10-marked ERGIC.

a, Immunofluorescence of HEK293T cells with expression of GFP1-10-TMED10 alone or together with mIL-1β-3×GFP11. Immunofluorescence was examined with anti-GFP antibody. Scale bar, 3 μm. b, The gating Strategy in flow cytometry. c, The HEK293T cells expressing GFP(1–10)-TMED10 and mIL-1β/mIL-1β WY/LL-3×GFP11. Fluorescence-activated cell sorting (FACS) analysis was performed to determine the complemented GFP signal. The GFP signal was quantified (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments). Immunoblot checking the expression of the indicated plasmids are shown in the right. d, Immunofluorescence of HEK293T cells with expression of mIL-1β-FLAG and mRuby2-TMED10. Immunofluorescence was examined with anti-Rab1A/1B/2A and anti-FLAG antibody. The cells were permeabilized with digitonin before fixation. Scale bar, 3 μm. e, Immunofluorescence of HeLa cells with expression of mIL-1β-FLAG and TMED10-V5 with or without BFA treatment (0.5 ng/μL). Scale bar, 5 μm. The quantification of the percentage of mIL-1β in TMED10 is shown in the right (mean ± SD). P values are indicated (two-tailed t test, n=50 cells, ns: no significant difference). f, GST-TMED10 proteoliposomes with or without T7-Rab1A were incubated with mIL-1β-FLAG alone or with the addition of GTP or GDP. Proteinase K digestion was performed to determine the amount of membrane-protected mIL-1β. g, GST-TMED10 proteoliposomes with or without T7-Rab1B were incubated with mIL-1β-FLAG alone or with the addition of GTP or GDP. Proteinase K digestion was performed to determine the amount of membrane-protected mIL-1β. h, GST-TMED10 proteoliposomes with or without T7-Rab1B were incubated with mIL-1β-FLAG or mIL-1β WY/LL-FLAG alone or with the addition of GTP. Proteinase K digestion was performed to determine the amount of membrane-protected mIL-1β. i, GST-TMED10 or GST-TMED10ΔCT proteoliposomes with or without T7-Rab1B were incubated with mIL-1β-FLAG alone or with the addition of GTP. Proteinase K digestion was performed to determine the amount of membrane-protected mIL-1β. f–i, The data are representatives of three independent experiments. Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

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Extended Data Fig. 7 TMED10-positive ERGIC compartment is required for UcPS.

a, SIM analysis and 3D view of GFP-ERGIC53 and TMED10-V5 in HeLa cells. Scale bar, 5 μm in overview and 2 μm in the zoomed in. b, SIM analysis of colocalization of TMED10 regions separated from ERGIC53 with GM130, SEC16, COPB2, SEC31, Rab5A, Rab7A or Rab2A. Scale bar, 5 μm in overview and 1 μm in the zoomed in. c, SIM analysis of colocalization of ssGFP with ERGIC53 or TMED10. Scale bar, 5 μm in overview and 2 μm in the zoomed in. Diagram showing the percentage of ssGFP colocalized with ERGIC53 or TMED10 per cell. P values are indicated (two-tailed t test, n=51 cells). d,e, IL-36α (d)/IL-33 (e) secretion in HEK293T cells using RUSH system. Diagram showing the quantification of secretion (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments). *, Non-specific band. L, low exposure; H, high exposure. f–h, ssGFP (f)/IL-6 (g)/IL-10 (h) secretion in HEK293T cells using RUSH system. Diagram showing the quantification of secretion (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments, ns, no significant difference). *, Non-specific band. i, SIM analysis of colocalization of GM130 with ERGIC53 or TMED10. Scale bar, 5 μm in overview and 2 μm in the zoomed in. Diagram showing the percentage of GM130 colocalized with ERGIC53 or TMED10 per cell. P values are indicated (two-tailed t test, n=52 cells). Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

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Extended Data Fig. 8 Rab2 promotes ERGIC compartmentalization positive for TMED10.

a, The HeLa cells stably expressing GFP-ERGIC53 and TMED10-V5 were transfected with BFP/BFP-Rab2A/Y3D. SIM analysis of compartmentalization of ERGIC53 and TMED10 with anti-V5 antibody. Scale bar, 5 μm in overview and 2 μm in the zoomed in. Diagram showing the percentage of TMED10 separated from ERGIC53 per cell (mean ± SD). P values are indicated (two-tailed t test, n=52 cells). b, The COS-7 cells were coexpressing GFP-ERGIC53, TMED10-V5 and BFP/BFP-Rab1A/1B/2A. Immunofluorescence and SIM analysis of compartmentalization of ERGIC53 and TMED10 with anti-V5 antibody. Scale bar, 10 μm in overview and 5 μm in the zoomed in. c,d, The HEK293T cells were expressed with GFP–Rab2A alone or together with streptavidin-ERGIC53 and SBP–TMED10ΔGOLD with or without Biotin (40 μM). Immunoblots showing IL-36α (c)/IL-33 (d) secretion. Diagram showing normalized IL-1β secretion (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments). *, Non-specific band. L, low exposure; H, high exposure. e, The HEK293T cells were co-transfected with TMED10-V5 and BFP/BFP-Rab1A/1B/2A plasmids. Immunoblot showing the amounts of TMED10-V5 in the cell lysates and the ERGIC membrane fractions. The data are representative of three independent experiments. f, The HEK293T cells were transfected with control siRNA (si Ctr) or siRNAs against Rab1A/1B/2A, followed by expressing TMED10-V5. Immunoblot showing the amounts of TMED10-V5 in the cell lysates and the ERGIC membrane fractions. The data are representative of three independent experiments. e,f, R1A, Rab1A; R1B, Rab1B; R2A, Rab2A. Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

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Extended Data Fig. 9 ERGIC compartmentalization is dependent on microtubules.

a, Immunofluorescence and SIM analysis of GFP-ERGIC53 and Tubulin in HeLa cells with or without Nocodazole treatment (10 μM) using SPY555-tubulin. Scale bar, 5 μm. b, Immunofluorescence and SIM analysis of GFP-ERGIC53 and TMED10-V5 stably expressed in HeLa cells with or without Nocodazole treatment (10 μM) using anti-V5 antibody. Scale bar, 5 μm in overview and 1 μm in the zoomed in. Diagram showing the percentage of TMED10 separated from ERGIC53 (mean ± SD). P values are indicated (two-tailed t test, n=52 cells, ns, no significant difference). c, Secretion of mIL-1β in HEK293T cells transfected with mIL-1β-FLAG plasmid together with GFP/GFP–Rab2A plasmids with or without Nocodazole. Diagram showing the quantification of IL-1β secretion (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments, ns, no significant difference). d, Immunofluorescence and SIM analysis of GFP-ERGIC53 and TMED10-V5 stably expressed in HeLa cells with or without Cytochalasin B treatment (10 μM) using anti-V5 antibody. Actin was labelled with Phalloidin. Scale bar, 5 μm in overview and 2 μm in the zoomed in. e, Immunofluorescence and SIM analysis of GFP-ERGIC53 and TMED10-V5 stably expressed in HeLa cells with or without Latrunculin A treatment (0.4 μM) using anti-V5 antibody. Actin was labelled with Phalloidin. Scale bar, 5 μm in overview and 2 μm in the zoomed in. f, Secretion of mIL-1β in HEK293T cells transfected with mIL-1β-FLAG plasmid together with GFP/GFP–Rab2A plasmids with or without Cytochalasin B (10 μM). The data are representative of three independent experiments. g, Secretion of mIL-1β in HEK293T cells transfected with mIL-1β-FLAG plasmid together with GFP/GFP–Rab2A plasmids with or without Latrunculin A (0.4 μM). f,g, The data are representative of three independent experiments. h, Immunofluorescence and SIM analysis of GFP-ERGIC53 and TMED10-V5 stably expressed in HeLa cells with or without BFA treatment (0.5 ng/μL) using anti-V5 antibody and anti-Rab1A/1B/2A antibody. Scale bar, 5 μm in overview and 2 μm in the zoomed in. Diagram showing the percentage of TMED10 in ERGIC53 (mean ± SD). P values are indicated (two-tailed t test, n=50 cells, ns, no significant difference). Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

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Extended Data Fig. 10 KIF5B is required for ERGIC compartmentalization.

a, The HEK293T cells stably expressing mIL-1β-HA were transfected with indicated shRNA plasmids. 72h post transfection, the cells were harvested for knockdown efficiency test by qPCR. b, Immunofluorescence and SIM analysis of endogenous KIF5B, TMED10-V5 and BFP/BFP-Rab1A/1B in HeLa cells using anti-KIF5B and anti-V5 antibody. Scale bar, 5 μm in overview and 2 μm in the zoomed in. Diagram showing the percentage of KIF5B with TMED10 (mean ± SD). P values are indicated (two-tailed t test, n=50 cells, ns, no significant difference). c, Immunofluorescence and SIM analysis of endogenous KIF5B, TMED10-V5 and BFP/BFP-Rab2A in HeLa cells transfected with control shRNA (sh Ctr) or shRNA plasmids against Rab1A/1B/2B (sh Rab1A/1B/2B) using anti-KIF5B and anti-V5 antibody. Scale bar, 5 μm in overview and 2 μm in the zoomed in. Diagram showing the percentage of KIF5B with TMED10 (mean ± SD). P values are indicated (two-tailed t test, n=50 cells, ns, no significant difference). d–f, ssGFP (d)/IL-6 (e)/IL-10 (f) secretion in HEK293T cells co-transfected with GFP/KIF5B-GFP plasmids. g–i, ssGFP (g)/IL-6 (h)/IL-10 (i) secretion in HEK293T cells co-transfected with control shRNA (Ctr) or shRNA plasmids against KIF5B (KIF5B KD). j, The HEK293T cells of WT, KIF5B KD and Rab1B KD were transfected with GFP(1–10)-TMED10 and IL-1β-GFP11. FACS analysis was performed to determine the complemented GFP signal with cells that did not have IL-1β-GFP11 expression as a negative control. Diagram showing the quantification of GFP signal (mean ± SD). P values are indicated (two-tailed t test, n=3 experiments, ns, no significant difference). Immunoblot showing the expression of the indicated proteins. k, CoIP analysis using HEK293T cells with GFP/GFP–Rab2A and endogenous KIF3B. l, CoIP analysis using HEK293T cells with TMED10-V5 and endogenous KIF5B with or without BFP-Rab2A overexpression. *, Non-specific band. d–i,k,l, The data are representative of three independent experiments. Exact P values are presented in Source numerical data. Source numerical data and unprocessed blots are available in Source data.

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Supplementary information

Reporting Summary

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Supplementary Table 1

Information on the siRNA, shRNA and quantitative PCR primers used in this study.

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Sun, Y., Tao, X., Han, Y. et al. A dual role of ERGIC-localized Rabs in TMED10-mediated unconventional protein secretion. Nat Cell Biol 26, 1077–1092 (2024). https://doi.org/10.1038/s41556-024-01445-4

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