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Migrasome Formation Is Mediated by Assembly of Micron-Scale Tetraspanin Macrodomains

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Migrasome Formation Is Mediated by Assembly of Micron-Scale Tetraspanin Macrodomains ARTICLES https://doi.org/10.1038/s41556-019-0367-5 Corrected: Publisher Correction Migrasome formation is mediated by assembly of micron-scale tetraspanin macrodomains Yuwei Huang1,2,6, Ben Zucker3,6, Shaojin Zhang1,2,6, Sharon Elias3, Yun Zhu4, Hui Chen5, Tianlun Ding1,2, Ying Li1,2, Yujie Sun4, Jizhong Lou5, Michael M. Kozlov 3* and Li Yu 1,2* Migrasomes are recently discovered cellular organelles that form as large vesicle-like structures on retraction fibres of migrat- ing cells. While the process of migrasome formation has been described before, the molecular mechanism underlying migra- some biogenesis remains unclear. Here, we propose that the mechanism of migrasome formation consists of the assembly of tetraspanin- and cholesterol-enriched membrane microdomains into micron-scale macrodomains, which swell into migra- somes. The major finding underlying the mechanism is that tetraspanins and cholesterol are necessary and sufficient for migra- some formation. We demonstrate the necessity of tetraspanins and cholesterol via live-cell experiments, and their sufficiency by generating migrasome-like structures in reconstituted membrane systems. We substantiate the mechanism by a theoretical model proposing that the key factor driving migrasome formation is the elevated membrane stiffness of the tetraspanin- and cholesterol-enriched macrodomains. Finally, the theoretical model was quantitatively validated by experimental demonstration of the membrane-stiffening effect of tetraspanin 4 and cholesterol. igrasomes are recently discovered cellular organelles whose To study whether the TSPAN4 expression level can affect mig- formation is closely associated with cell migration. When rasome formation, we established three normal rat kidney (NRK) Mcells crawl on extracellular substrates, long membrane pro- epithelial cell lines that stably express different levels of TSPAN4 jections, referred to as retraction fibres (RFs), are pulled out of the and green fluorescent protein (GFP) (Fig. 1b,d; Supplementary plasma membrane at the rear of the cell1. The RFs serve as tethers Fig. 1a). We found that overexpression of TSPAN4 enhanced mig- stretched between the cell body and the substrate2. Migrasomes are rasome formation in a dose-dependent manner (Fig. 1b,c). It is large vesicle-like structures that start to grow on the RFs hours after the worth noting that TSPAN4-GFP appears as a smeared double band initiation of RF formation3. Eventually, as the cell migrates away, the on western blots, which is a result of glycosylation (Supplementary connections between the cell and the RFs break, the RFs disintegrate Fig. 1b). Among the nine tetraspanins that can significantly induce and the migrasomes detach from the cell. During zebrafish gastru- migrasome formation, TSPAN4 was the most highly expressed in lation, migrasomes release developmental cues, including CXCL12, human gastric carcinoma MGC-803 cells (Supplementary Fig. 1c) into defined locations in embryos to modulate organ morphogen- and NRK cells (Supplementary Table 1). esis4. Thus, migrasomes have been proposed to provide a mechanism To test whether TSPAN4 is required for migrasome forma- for integrating and relaying spatiotemporal chemical information for tion, we generated TSPAN4 knockout cell lines using the clustered cell–cell communication4. So far, the molecular mechanism underly- regularly interspaced short palindromic repeats (CRISPR)–Cas9 ing migrasome formation has never been addressed. technique. Knockout of TSPAN4 did indeed impair migra- Tetraspanin 4 (TSPAN4) was previously shown to be abundant some formation in MGC-803 cells (Fig. 1e–g) and NRK cells in the migrasome membrane2. Proteins of the tetraspanin family, (Supplementary Fig. 1d,e). which has 33 members, are present in every cell type, and all of Altogether, these data suggest that tetraspanins are necessary them contain four transmembrane domains5. Tetraspanins can lat- for migrasome formation. It is worth noting that in L929 cells erally segregate in the membrane plane into tetraspanin-enriched (NCTC clone 929 of strain L, mouse connective tissue), knock- microdomains (TEMs)6, which are around 100 nm in size, and con- ing out Tspan4 did not impair migrasome formation, presumably tain, in addition to tetraspanins, a high concentration of cholesterol due to the presence of other migrasome-forming tetraspanins and a set of tetraspanin-associated proteins7,8. (Supplementary Fig. 1f). Results Dynamics of TSPAN4 recruitment to migrasomes during mig- TSPAN4 is necessary for migrasome formation. We found that rasome formation. Next, we studied the dynamics of TSPAN4 overexpression of 14 out of the 33 known mammalian tetraspan- repartitioning on RF membranes during the course of migrasome ins enhanced migrasome formation (Fig. 1a). Among these 14 tet- biogenesis. First, we measured the mean fluorescence intensity of raspanins, 9 had a strong effect (Fig. 1a). Since TSPAN4 is one of TSPAN4-GFP on migrasomes and RFs. We found that during the most effective tetraspanins for migrasome induction, we chose it for rapid initial phase of migrasome growth, the mean intensity of in-depth study. TSPAN4-GFP rose on migrasomes, while it slightly decreased on 1The State Key Laboratory of Membrane Biology, Tsinghua University–Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. 2Beijing Frontier Research Center for Biological Structure, Beijing, China. 3Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 4The State Key Laboratory of Membrane Biology, Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China. 5Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. 6These authors contributed equally: Yuwei Huang, Ben Zucker, Shaojin Zhang. *e-mail: [email protected]; [email protected] NATURE CELL BIOLOGY | VOL 21 | AUGUST 2019 | 991–1002 | www.nature.com/naturecellbiology 991 ARTICLES NATURE CELL BIOLOGY a 40 *** ** 30 * NS 20 10 8 6 4 Migrasomes number 2 0 CD9 CD82CD81 CD53 CD37 CD63 Vector CD151 TSPAN1TSPAN2TSPAN4TSPAN6TSPAN7TSPAN9 TSPAN3TSPAN5 TSPAN8 TSPAN18 TSPAN13 TSPAN10TSPAN11TSPAN12TSPAN14TSPAN15TSPAN16TSPAN17TSPAN19TSPAN20TSPAN21TSPAN22TSPAN23 TSPAN31TSPAN32TSPAN33 b c No. 10 No. 42 No. 20 8 P < 0.0001 P < 0.0001 *** 6 *** 4 m RF length µ 2 No. migrosomes per 100 0 No. 10 No. 42 No. 20 d No. 10 No. 42 No. 20 f P < 0.0001 kDa 1.5 *** 70 TSPAN4-GFP 1.0 55 m RF length µ 55 0.5 β-actin 36 No. migrosomes per 100 0.0 Wild type TSPAN4 KO e g Wild type TSPAN4 KO Kb WT TSPAN4 KO 5 2 1 0.5 0.25 0.1 Fig. 1 | TSPAN4 is necessary for migrasome formation. a, All 33 members of the tetraspanin family were analysed for their ability to induce migrasome formation following overexpression in NRK cells. Migrasome numbers were quantified based on fluorescent images taken by confocal microscopy. The experiment was done once. Data shown represent the mean ± s.e.m.; n ≥ 100 cells. *P < 0.05, **P < 0.01, ***P < 0.001. Red outlines, groups showed significant difference; black outlines, groups showed no significant difference. Exact sample sizes and P values are presented in Supplementary Table 4. b, NRK cells (cell numbers 10, 42 and 20) stably expressing different levels of TSPAN4-GFP were analysed for the number of migrasomes by confocal microscopy. Scale bar, 10 µm. c, The number of migrasomes per 100 µm of RF from images like those shown in b was quantified. Data shown represent the mean ± s.e.m.; n = 54 (no. 10), 47 (no. 42) and 54 (no. 20) cells, each pooled from 3 independent experiments. d, The TSPAN4-GFP expression level of cell lines from b was analysed by western blotting. e, A TSPAN4 knockout (KO) MGC-803 cell line was established using the CRISPR–Cas9 technique. Wild- type (WT) and TSPAN4 KO cells were analysed by confocal microscopy for the number of migrasomes. Scale bar, 10 µm. f, Cells from WT and TSPAN4 KO MGC-803 cells were quantified for the migrasome number per 100 µm of RFs. Data shown represent the mean ± s.e.m.; n = 100 cells for each genotype, each pooled from 3 independent experiments. g, Verification of the MGC-803 TSPAN4 KO cell line by PCR. The unprocessed blots images related to d are presented in Supplementary Fig. 6. Experiments related to b–g were independently repeated three times. Two-tailed unpaired t-tests were used for statistical analyses. The statistical details for a, c and f are available in Supplementary Table 4. RFs (Fig. 2a,b). After the migrasomes reached their maximal size, signal did not recover at all (Fig. 2c; Supplementary Fig. 2a–c). These the mean intensity of migrasomal TSPAN4-GFP remained constant results further support the conclusion that TSPAN4 is recruited to (Fig. 2a,b). The migrasomal state characterized by a constant size migrasomes during the growth phase. The recruitment of TSPAN4 and TSPAN4 intensity will be referred to as the steady phase. stops after a migrasome enters the steady phase. To substantiate this observation, we carried out fluorescence The recovery of bleached TSPAN4-GFP in migrasomes during recovery after photobleaching (FRAP) assays on migrasomes dur- the growth phase indicates that TSPAN4-GFP can be recruited from ing the growth and steady phases. We observed a fast recovery RFs to migrasomes. Next, we tested whether TSPAN4-GFP can also of the migrasomal TSPAN4 signal in the growth phase (Fig. 2c; move in the opposite direction; that is, from a migrasome
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