Julia von Blume, PhD
Research & Publications
Biography
News
Research Summary
The goal of our group is to elucidate molecular mechanisms how the Golgi apparatus sorts secreted proteins and how the underlying mechanisms are integrated with cell physiology. Secreted proteins include signaling molecules such as hormones, cytokines or chemokines, as well as extracellular matrix proteins such as collagens. Sorting of these proteins constitutes the fundamental basis of cellular biology and mistargeting causes a variety of diseases such as cancer, diabetes, and autoimmune diseases.
Extensive Research Description
How are secretory proteins sorted and targeted to the cell surface?
Most secreted proteins contain a signal sequence that targets them to the endoplasmic reticulum (ER) during synthesis. There they are translocated into the ER lumen and once folded travel in coat complex II (COPII)-coated vesicles to the Golgi apparatus. After passage through the Golgi membranes, proteins are sorted at the TGN for transport to their final destination. Depending on the cell types these destinations include apical and basolateral cell surfaces, early/sorting endosomes, late endosomes, recycling endosomes, secretory storage granules and preceding Golgi compartments. Sorting of lysosomal hydrolases for delivery to pre-lysosomes is well established, the corresponding mechanism by which secreted proteins are sorted for transport to the plasma membrane is poorly understood.
- Ca2+ dependent sorting in the trans-Golgi Network
- The interconnection between Ca2+ dependent sorting and leukocyte trafficking
- Novel Ca2+ independent sorting pathways
In recent years we discovered a novel sorting mechanism of secretory proteins a process that had remained mysterious for decades. The major components regulating this process are F-actin, cofilin, the Golgi ATPase SPCA1, Ca2+, and Cab45. We reconstituted the binding of cofilin to SPCA1 that recruits F-actin to a specific domain to initiate a Ca2+ influx required for cargo sorting Next, we discovered how a Golgi resident protein Cab45 binds and sorts cargo molecules by selective Ca2+ dependent oligomerization. This discovery led to the critical concept of sorting of proteins independent of a classical sorting receptor. Our research focuses on the poorly understood sorting reactions in the trans-Golgi Network (TGN) with particular emphasis on the role of protein and lipid complexes that recognize and pack secreted proteins into specific transport carriers. This process is crucial to facilitate secretion and function of these proteins in different cell types and organisms. Moving forward, we plan to identify the molecular mechanisms facilitating Ca2+ dependent sorting applying a combination of cell-based experiments, high-end microscopy, and biochemical reconstitution assays. To further investigate the link between TGN dependent sorting and physiology such as diabetes, we will apply mouse models.
A second major research goal of the group is the investigation of the interconnection of Ca2+ dependent sorting and cell migration in leukocytes. Leukocyte trafficking positions immune cells in the body and therefore has a central role in the function of the immune system. The foundation of these studies is that Cab45 and SPCA1 are primary regulators of extravasation of leukocytes. Leukocyte extravasation requires the sorting and transport of a so far unknown specific set of soluble molecules in the TGN. We plan to identify and analyze the secretomes of primary leukocytes isolated from SPCA1 and Cab45 knock-out mice. Having identified these factors, we will reconstitute their sorting using biochemical assays to gain an insight into the molecular complex in the TGN that together with Cab45 steers this process. Moving forward, we will be able to monitor the significance of Cab45, SPCA1 and the new components for extravasation of leukocytes in living organisms using intravital microscopy. These experiments will give mechanistic insight into the importance of TGN sorting for macrophage extravasation and will thus explain the basic mechanism of innate immunity.
In a third approach, we investigate additional mechanisms of TGN based secretory cargo sorting. For instance, our unpublished work has shown that sorting of Matrix Metallo Proteinases (MMPs) to podosomes in macrophages occurs in independently of our Ca2+-dependent sorting. We have accomplished to identify novel sorting regulators required for the transport of MMP2 to podosomes. To monitor and investigate the role of a physiological system we generated estrogen-regulated Hoxb8 immortalized macrophages in which we use CRISPR/Cas9 deplete these components. This system will allow monitoring the trafficking of MMP2 in macrophages and will also enable to track their movement in living organisms. These data will give an insight into the relevance of sorting of proteins inside macrophages and will allow testing their role in matrix invasion in normal and cancer tissues.
Selected Publications
- Quantification of Protein Exit at the Trans-Golgi NetworkTran M, Kim Y, von Blume J. Quantification of Protein Exit at the Trans-Golgi Network. 2022, 2557: 583-594. PMID: 36512239, DOI: 10.1007/978-1-0716-2639-9_35.
- Liquid–liquid phase separation facilitates the biogenesis of secretory storage granulesParchure A, Tian M, Stalder D, Boyer C, Bearrows S, Rohli K, Zhang J, Rivera-Molina F, Ramazanov B, Mahata S, Wang Y, Stephens S, Gershlick D, von Blume J. Liquid–liquid phase separation facilitates the biogenesis of secretory storage granules. Journal Of Cell Biology 2022, 221: e202206132. PMID: 36173346, PMCID: PMC9526250, DOI: 10.1083/jcb.202206132.
- Cargo sorting at the trans-Golgi network at a glanceFord C, Parchure A, von Blume J, Burd CG. Cargo sorting at the trans-Golgi network at a glance. Journal Of Cell Science 2021, 134 PMID: 34870705, PMCID: PMC8714066, DOI: 10.1242/jcs.259110.
- Calcium levels in the Golgi complex regulate clustering and apical sorting of GPI-APs in polarized epithelial cellsLebreton S, Paladino S, Liu D, Nitti M, von Blume J, Pinton P, Zurzolo C. Calcium levels in the Golgi complex regulate clustering and apical sorting of GPI-APs in polarized epithelial cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2014709118. PMID: 34389665, PMCID: PMC8379914, DOI: 10.1073/pnas.2014709118.
- Retention Using Selective Hooks (RUSH) Cargo Sorting Assay for Live-cell Vesicle Tracking in the Secretory Pathway Using HeLa Cells.Pakdel M, Pacheco-Fernandez N, von Blume J. Retention Using Selective Hooks (RUSH) Cargo Sorting Assay for Live-cell Vesicle Tracking in the Secretory Pathway Using HeLa Cells. Bio-protocol 2021, 11: e3958. PMID: 33855118, PMCID: PMC8032492, DOI: 10.21769/bioprotoc.3958.
- Sending out molecules from the TGNRamazanov BR, Tran ML, von Blume J. Sending out molecules from the TGN. Current Opinion In Cell Biology 2021, 71: 55-62. PMID: 33706234, PMCID: PMC8328904, DOI: 10.1016/j.ceb.2021.02.005.
- Retention Using Selective Hooks (RUSH) Cargo Sorting Assay for Protein Vesicle Tracking in HeLa Cells.Pacheco-Fernandez N, Pakdel M, Von Blume J. Retention Using Selective Hooks (RUSH) Cargo Sorting Assay for Protein Vesicle Tracking in HeLa Cells. Bio-protocol 2021, 11: e3936. PMID: 33796610, PMCID: PMC8005885, DOI: 10.21769/bioprotoc.3936.
- Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3Pigoni M, Hsia H, Hartmann J, Njavro J, Shmueli MD, Müller SA, Güner G, Tüshaus J, Kuhn P, Kumar R, Gao P, Tran ML, Ramazanov B, Blank B, Ederveen A, Von Blume J, Mulle C, Gunnersen JM, Wuhrer M, Rammes G, Busche MA, Koeglsperger T, Lichtenthaler SF. Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3. The EMBO Journal 2020, 39: e103457. PMID: 32567721, PMCID: PMC7396870, DOI: 10.15252/embj.2019103457.
- Nucleobindin-1 regulates ECM degradation by promoting intra-Golgi trafficking of MMPsPacheco-Fernandez N, Pakdel M, Blank B, Sanchez-Gonzalez I, Weber K, Tran ML, Hecht TK, Gautsch R, Beck G, Perez F, Hausser A, Linder S, von Blume J. Nucleobindin-1 regulates ECM degradation by promoting intra-Golgi trafficking of MMPs. Journal Of Cell Biology 2020, 219: e201907058. PMID: 32479594, PMCID: PMC7401813, DOI: 10.1083/jcb.201907058.
- Fam20C regulates protein secretion by Cab45 phosphorylationHecht TK, Blank B, Steger M, Lopez V, Beck G, Ramazanov B, Mann M, Tagliabracci V, von Blume J. Fam20C regulates protein secretion by Cab45 phosphorylation. Journal Of Cell Biology 2020, 219: e201910089. PMID: 32422653, PMCID: PMC7265331, DOI: 10.1083/jcb.201910089.
- Lipid‐dependent coupling of secretory cargo sorting and trafficking at the trans‐Golgi networkvon Blume J, Hausser A. Lipid‐dependent coupling of secretory cargo sorting and trafficking at the trans‐Golgi network. FEBS Letters 2019, 593: 2412-2427. PMID: 31344259, PMCID: PMC8048779, DOI: 10.1002/1873-3468.13552.
- Signal peptide peptidase‐like 2c impairs vesicular transport and cleaves SNARE proteinsPapadopoulou AA, Müller SA, Mentrup T, Shmueli MD, Niemeyer J, Haug-Kröper M, von Blume J, Mayerhofer A, Feederle R, Schröder B, Lichtenthaler SF, Fluhrer R. Signal peptide peptidase‐like 2c impairs vesicular transport and cleaves SNARE proteins. EMBO Reports 2019, 20 PMID: 31061204, PMCID: PMC6500957, DOI: 10.15252/embr.201948133.
- Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell deathSilvestre-Roig C, Braster Q, Wichapong K, Lee EY, Teulon JM, Berrebeh N, Winter J, Adrover JM, Santos GS, Froese A, Lemnitzer P, Ortega-Gómez A, Chevre R, Marschner J, Schumski A, Winter C, Perez-Olivares L, Pan C, Paulin N, Schoufour T, Hartwig H, González-Ramos S, Kamp F, Megens RTA, Mowen KA, Gunzer M, Maegdefessel L, Hackeng T, Lutgens E, Daemen M, von Blume J, Anders HJ, Nikolaev VO, Pellequer JL, Weber C, Hidalgo A, Nicolaes GAF, Wong GCL, Soehnlein O. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature 2019, 569: 236-240. PMID: 31043745, PMCID: PMC6716525, DOI: 10.1038/s41586-019-1167-6.
- Organelle zonesNakano A, von Blume J. Organelle zones. Molecular Biology Of The Cell 2019, 30: 731-731. PMID: 30870094, PMCID: PMC6589774, DOI: 10.1091/mbc.e18-12-0818.
- Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins.Papadopoulou AA, Müller SA, Mentrup T, Shmueli MD, Niemeyer J, Haug-Kröper M, von Blume J, Mayerhofer A, Feederle R, Schröder B, Lichtenthaler SF, Fluhrer R. Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins. EMBO Reports 2019, 20: e46451. PMID: 32048434, DOI: 10.15252/embr.201846451.
- Meeting Report From the 2019 “Organelle Zone” Symposium in Osaka, JapanLevine TP, Perez F, Saheki Y, von Blume J. Meeting Report From the 2019 “Organelle Zone” Symposium in Osaka, Japan. Contact 2019, 2: 2515256419877091. PMID: 31588423, PMCID: PMC6778051, DOI: 10.1177/2515256419877091.
- Activity of the SPCA1 Calcium Pump Couples Sphingomyelin Synthesis to Sorting of Secretory Proteins in the Trans-Golgi NetworkDeng Y, Pakdel M, Blank B, Sundberg EL, Burd CG, von Blume J. Activity of the SPCA1 Calcium Pump Couples Sphingomyelin Synthesis to Sorting of Secretory Proteins in the Trans-Golgi Network. Developmental Cell 2018, 47: 464-478.e8. PMID: 30393074, PMCID: PMC6261503, DOI: 10.1016/j.devcel.2018.10.012.
- Exploring new routes for secretory protein export from the trans-Golgi networkPakdel M, von Blume J. Exploring new routes for secretory protein export from the trans-Golgi network. Molecular Biology Of The Cell 2018, 29: 235-240. PMID: 29382805, PMCID: PMC5996961, DOI: 10.1091/mbc.e17-02-0117.
- Persistent inhibition of pore-based cell migration by sub-toxic doses of miuraenamide, an actin filament stabilizerMoser C, Rüdiger D, Förster F, von Blume J, Yu P, Kuster B, Kazmaier U, Vollmar AM, Zahler S. Persistent inhibition of pore-based cell migration by sub-toxic doses of miuraenamide, an actin filament stabilizer. Scientific Reports 2017, 7: 16407. PMID: 29180826, PMCID: PMC5703899, DOI: 10.1038/s41598-017-16759-7.
- Cab45—Unraveling key features of a novel secretory cargo sorter at the trans-Golgi networkBlank B, von Blume J. Cab45—Unraveling key features of a novel secretory cargo sorter at the trans-Golgi network. European Journal Of Cell Biology 2017, 96: 383-390. PMID: 28372832, DOI: 10.1016/j.ejcb.2017.03.001.
- Secretory cargo sorting by Ca2+-dependent Cab45 oligomerization at the trans-Golgi networkCrevenna AH, Blank B, Maiser A, Emin D, Prescher J, Beck G, Kienzle C, Bartnik K, Habermann B, Pakdel M, Leonhardt H, Lamb DC, von Blume J. Secretory cargo sorting by Ca2+-dependent Cab45 oligomerization at the trans-Golgi network. Journal Of Cell Biology 2016, 213: 305-314. PMID: 27138253, PMCID: PMC4862333, DOI: 10.1083/jcb.201601089.
- Julia von Blume: Sorting through the trans-Golgivon Blume J, Sedwick C. Julia von Blume: Sorting through the trans-Golgi. Journal Of Cell Biology 2015, 208: 4-5. PMID: 25559180, PMCID: PMC4284231, DOI: 10.1083/jcb.2081pi.
- Cofilin recruits F-actin to SPCA1 and promotes Ca2+-mediated secretory cargo sortingKienzle C, Basnet N, Crevenna AH, Beck G, Habermann B, Mizuno N, von Blume J. Cofilin recruits F-actin to SPCA1 and promotes Ca2+-mediated secretory cargo sorting. Journal Of Cell Biology 2014, 206: 635-654. PMID: 25179631, PMCID: PMC4151145, DOI: 10.1083/jcb.201311052.
- JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropeniaBoztug K, Järvinen PM, Salzer E, Racek T, Mönch S, Garncarz W, Gertz EM, Schäffer AA, Antonopoulos A, Haslam SM, Schieck L, Puchałka J, Diestelhorst J, Appaswamy G, Lescoeur B, Giambruno R, Bigenzahn JW, Elling U, Pfeifer D, Conde CD, Albert MH, Welte K, Brandes G, Sherkat R, van der Werff ten Bosch J, Rezaei N, Etzioni A, Bellanné-Chantelot C, Superti-Furga G, Penninger JM, Bennett KL, von Blume J, Dell A, Donadieu J, Klein C. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nature Genetics 2014, 46: 1021-1027. PMID: 25129144, PMCID: PMC4829076, DOI: 10.1038/ng.3069.
- Secretory cargo sorting at the trans-Golgi networkKienzle C, von Blume J. Secretory cargo sorting at the trans-Golgi network. Trends In Cell Biology 2014, 24: 584-593. PMID: 24841758, DOI: 10.1016/j.tcb.2014.04.007.
- Directing Traffic into the FutureAntonny B, Audhya J, l Bagnat M, von Blume J, Briggs JA, Giraudo C, Kaeser PS, Miller E, Reinisch K, Sbalzarini IF, Schuldiner M, Shen J, Takamori S, Verstreken P, Walther T. Directing Traffic into the Future. Developmental Cell 2013, 27: 480-484. PMID: 24482802, DOI: 10.1016/j.devcel.2013.11.017.
- Deficiency Of JAGN1 Causes Severe Congenital Neutropenia Associated With Defective Secretory Pathway and Aberrant Myeloid Cell HomeostasisBoztug K, Järvinen P, Salzer E, Racek T, Mönch S, Garncarz W, Gertz E, Schäffer A, Antonopoulos A, Haslam S, Ziesenitz L, Puchalka J, Diestelhorst J, Appaswamy G, Lescoeur B, Giambruno R, Bigenzahn J, Elling U, Pfeifer D, Welte K, Brandes G, Sherkat R, Van der Werff Ten Bosch J, Rezaei N, Etzioni A, Bellanne-Chantelot C, Superti-Furga G, Bennett K, von Blume J, Dell A, Donadieu J, Klein C. Deficiency Of JAGN1 Causes Severe Congenital Neutropenia Associated With Defective Secretory Pathway and Aberrant Myeloid Cell Homeostasis. Blood 2013, 122: 439. DOI: 10.1182/blood.v122.21.439.439.
- Cab45 is required for Ca2+-dependent secretory cargo sorting at the trans-Golgi networkvon Blume J, Alleaume AM, Kienzle C, Carreras-Sureda A, Valverde M, Malhotra V. Cab45 is required for Ca2+-dependent secretory cargo sorting at the trans-Golgi network. Journal Of Cell Biology 2012, 199: 1057-1066. PMID: 23266954, PMCID: PMC3529532, DOI: 10.1083/jcb.201207180.
- Cofilin-mediated sorting and export of specific cargo from the Golgi apparatus in yeastCurwin AJ, von Blume J, Malhotra V. Cofilin-mediated sorting and export of specific cargo from the Golgi apparatus in yeast. Molecular Biology Of The Cell 2012, 23: 2327-2338. PMID: 22553351, PMCID: PMC3374751, DOI: 10.1091/mbc.e11-09-0826.
- ADF/Cofilin Regulates Secretory Cargo Sorting at the TGN via the Ca2+ ATPase SPCA1von Blume J, Alleaume AM, Cantero-Recasens G, Curwin A, Carreras-Sureda A, Zimmermann T, van Galen J, Wakana Y, Valverde MA, Malhotra V. ADF/Cofilin Regulates Secretory Cargo Sorting at the TGN via the Ca2+ ATPase SPCA1. Developmental Cell 2011, 20: 652-662. PMID: 21571222, DOI: 10.1016/j.devcel.2011.03.014.
- Role of the Second Cysteine-rich Domain and Pro275 in Protein Kinase D2 Interaction with ADP-Ribosylation Factor 1, Trans-Golgi Network Recruitment, and Protein TransportPusapati GV, Krndija D, Armacki M, von Wichert G, von Blume J, Malhotra V, Adler G, Seufferlein T. Role of the Second Cysteine-rich Domain and Pro275 in Protein Kinase D2 Interaction with ADP-Ribosylation Factor 1, Trans-Golgi Network Recruitment, and Protein Transport. Molecular Biology Of The Cell 2010, 21: 1011-1022. PMID: 20089835, PMCID: PMC2836954, DOI: 10.1091/mbc.e09-09-0814.
- Actin remodeling by ADF/cofilin is required for cargo sorting at the trans-Golgi networkvon Blume J, Duran JM, Forlanelli E, Alleaume AM, Egorov M, Polishchuk R, Molina H, Malhotra V. Actin remodeling by ADF/cofilin is required for cargo sorting at the trans-Golgi network. Journal Of Cell Biology 2009, 187: 1055-1069. PMID: 20026655, PMCID: PMC2806282, DOI: 10.1083/jcb.200908040.
- Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cellsvon Wichert G, Edenfeld T, von Blume J, Krisp H, Krndija D, Schmid H, Oswald F, Lother U, Walther P, Adler G, Seufferlein T. Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells. Cellular Signalling 2008, 20: 925-934. PMID: 18262756, DOI: 10.1016/j.cellsig.2008.01.003.
- Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2von Blume J, Knippschild U, Dequiedt F, Giamas G, Beck A, Auer A, Van Lint J, Adler G, Seufferlein T. Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. The EMBO Journal 2007, 26: 4619-4633. PMID: 17962809, PMCID: PMC2080801, DOI: 10.1038/sj.emboj.7601891.
- New Role for hPar-1 Kinases EMK and C-TAK1 in Regulating Localization and Activity of Class IIa Histone DeacetylasesDequiedt F, Martin M, Von Blume J, Vertommen D, Lecomte E, Mari N, Heinen MF, Bachmann M, Twizere JC, Huang MC, Rider MH, Piwnica-Worms H, Seufferlein T, Kettmann R. New Role for hPar-1 Kinases EMK and C-TAK1 in Regulating Localization and Activity of Class IIa Histone Deacetylases. Molecular And Cellular Biology 2006, 26: 7086-7102. PMID: 16980613, PMCID: PMC1592903, DOI: 10.1128/mcb.00231-06.
- Protein Kinase D2 (PKD2) phosphoryliert Histon Deacetylase 7 (HDAC7) und aktiviert Nur77 in humanen Magenkarzinomzellenvon Blume J, Dequiedt F, Adler G, Seufferlein T. Protein Kinase D2 (PKD2) phosphoryliert Histon Deacetylase 7 (HDAC7) und aktiviert Nur77 in humanen Magenkarzinomzellen. Zeitschrift Für Gastroenterologie 2006, 44 DOI: 10.1055/s-2006-950905.
- Role of the Regulatory Domain of Protein Kinase D2 in Phorbol Ester Binding, Catalytic Activity, and Nucleocytoplasmic ShuttlingAuer A, von Blume J, Sturany S, von Wichert G, Van Lint J, Vandenheede J, Adler G, Seufferlein T. Role of the Regulatory Domain of Protein Kinase D2 in Phorbol Ester Binding, Catalytic Activity, and Nucleocytoplasmic Shuttling. Molecular Biology Of The Cell 2005, 16: 4375-4385. PMID: 15975900, PMCID: PMC1196345, DOI: 10.1091/mbc.e05-03-0251.