Aftab Nadeem Lab

All living cells are dependent on functional biological membranes for their survival. Cell membranes are essential structural elements in all kingdoms of life. The cell membrane separates the extracellular environment from the intracellular space, where biochemical processes important for cellular life occur. The eukaryotic cell membrane is a highly dynamic barrier between the cell and its surroundings, responsible for a variety of biological functions, including molecular transport and activation of intracellular signaling cascades important to cell proliferation.

Lipids in the cell membrane are of particular importance as they have a critical role in membrane microdomain architecture, and membrane trafficking. These properties make lipids an appealing target for bacterial pathogens attempting to modulate host cell activities in order to survive and thrive. Several lines of evidence suggest that lipids have a crucial role in different phases of host–pathogen interactions. Microbial proteins, including bacterial toxins and viral components such as the SARS-CoV-2 spike protein, bind to the host cell membrane and introduce lipid membrane perturbations that contribute to the severity of the infection process.

Pore-forming protein toxins (PFTs) secreted by a wide range of bacterial pathogens represent a special class of membrane-damaging proteins. They exert their cytolytic effects by punching 'holes' into the target cell membrane, thus destroying the cell membrane. This process causes lysis, killing of the target cell. PFTs are mainly synthesized as water-soluble monomeric molecules, and in contact with target cell membranes, they undergo conformational change and form membrane-inserted oligomeric pores. Interestingly, we recently discovered a previously unknown phenomenon of cell membrane tubulation by an α-PFT MakA (motility-associated killing factor A), secreted by cholera baacteria Vibrio cholerae.

In my lab, we aim to better understand the molecular mechanisms through which microbial proteins affect lipid membranes.

Specific aims:

1) To investigate the mechanisms involved in the tubulation of lipid membranes by α-PFTs.

2) Mechanism(s) associated with the cellular responses triggered by α-PFTs.

3) To understand the role of microbial protein-lipid interactions in host cell

pathogenesis.

4) Biotechnological applications of bacterial α-PFTs.

Scientific publications and patents

Peer-reviewed articles

1.    Nadeem A*, Berg A, Pace H, Alam A, Toh E, Åden J, Zlatkov N, Myint SL, Persson K, Gröbner G, Sjöstedt A, Bally M, Barandun J, Uhlin BE*, Wai SN* (2022). Protein-lipid interaction at low pH induces oligomerisation of the MakA cytotoxin from Vibrio cholerae. Elife, 11:e73439. doi: 10.7554/eLife.73439. *co-corresponding author

2.    Toh E, Baryalai P, Nadeem A, Aung KM, Chen S, Persson K, Persson JL, Uhlin BE, Wai SN. Bacterial protein MakA causes suppression of tumor cell proliferation via inhibition of PIP5K1α/Akt signalling. Cell Death and Dis, 13:1024 ; doi.org/10.1038/s41419-022-05480-7

3.    Liu Y, Nadeem A, Sebastian S, Olsson M, Styring E， Isaksson H, Tägil M, Lidgren L, Raina DB. Bone mineral: A trojan horse for bone cancers. Efficient mitochondria targeted delivery and tumor eradication with nano hydroxyapatite containing doxorubicin. Mater Today Bio, doi: 10.1016/j.mtbio.2022.100227.

4. Hansen CF, Nadeem A, Schmidtchen A, van der Plas MJA (2022). Differential internalization of thrombin-derived host defense into monocytes and macrophages. J Innate Immun, 14(5):418-432.

5. Nadeem A*, Nagampalli R*, Eric T, Alam A, Myint SL, Heidler T, Dongre M, Zlatkov N, Pace H, Bano D, Sjöstedt A, Bally M, Uhlin BE, Wai SN and Persson K (2021). A tripartite cytolytic toxin formed by Vibrio cholerae proteins with flagellum-facilitated secretion. Proc Natl Acad Sci U S A,  118(47):e2111418118. *Equal contribution

6. Nadeem A*, Alam T, Eric T, Myint SL, ur Rehman Z, Liu T, Bally M, Arnqvist A, Sjöstdt A, Wang H, Zhu J, Persson K, Uhlin BE, Wai SN* (2021). Phosphatidic acid-mediated binding and internalization of the V. cholerae cytotoxin MakA into host cells. PLoS Pathog, 17(3):e1009414. *co-corresponding author

7. Nadeem A*, Aung KM*, Ray T, Persson K, Pal A, Uhlin BE and Wai SN (2021). Suppression of β-catenin signaling in colon carcinoma cells by a bacterial protein. Int J Cancer, 149(2):442-459. *Equal contribution

8. Brisuda A, Ho JCS, Kandiyal PS, Ng JTY, Ambite I, Butler DSC, Hacek J, Wan MLY, Tran TH, Nadeem A, Tran TH, Hastings A, Storm P, Fortunati DL, Esmaeili P, Novotna H, Hornak J, Mu YG, Mok KH, Babjuk M and Svanborg C. (2021). Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex. Nat Commun, 12(1):3427.

9. Myint SL, Zlatkov N, Aung KM, Toh E, Sjöström A, Nadeem A, Duperthuy M, Uhlin BE, Wai SN. Ecotin and LamB in Escherichia coli influence the susceptibility to Type VI secretion-mediated interbacterial competition and killing by Vibrio cholerae (2021). Biochim Biophys Acta Gen Subj. 1865(7):129912.

10. Corkery DP*, Nadeem A*, Aung KM, Hassan A, Liu T, Cervantes R, Lystad AH, Wang H, Persson K, Puhar P, Simonsen A, Uhlin BE, Wai SN and Wu YW. (2020). The Vibrio cholerae cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy. J Cell Sci, 134(5):jcs252015 *Equal contribution

11. Joshi B, Singh B, Nadeem A, Askarian F, Wai SN, Johannessen M and Hegstad K. (2020). Transcriptome profiling of Staphylococcus aureus associated membrane-derived vesicles reveals presence of small RNA-cargo. Front Mol Biosci, 7:566207.

12. Ahmad I, Karah N, Nadeem A, Wai SN, Uhlin BE (2019). Analysis of colony phase variation switch in Acinetobacter baumannii clinical isolates. PLoS One. 4;14(1):e0210082. doi: 10.1371/journal.pone.0210082.

13. Nadeem A, Ho JCS, Tran TH, Paul S, Granqvist V, Despretz N and Svanborg C. (2019). Beta-sheet-specific interactions with heat shock proteins define a mechanism of delayed tumor cell death in response to HAMLET. J Mol Biol, 431, 2612–2627.

14. Butler DSC, Ambite I, Nagy K, Cafaro C, Ahmed A, Nadeem A, Filenko N, Tran TH, Andersson KE, Wullt B, Puthia M, Svanborg C (2018). Neuroepithelial control of mucosal inflammation in acute cystitis. Sci Rep, 2018 Jul 20;8(1):11015.

15. Ambite I, Puthia M, Nagy K, Cafaro C, Nadeem A, Rydström G, Zheng Y, Filenko N, Morin P, Butler D, Wullt B, Miethke T, Svanborg C. (2016). Molecular basis of acute cystitis reveals susceptibility genes and immunotherapeutic targets. PloS Pathog. 12(10):e1005848.

16. Puthia M, Ambite I, Cafaro C, Butler D, Huang Y, Lutay N, Rydström G, Gullstrand B, Swaminathan B, Nadeem A, Nilsson B, Svanborg C. (2016). IRF7 inhibition prevents destructive innate immunity - a target for non-antibiotic therapy of bacterial infections. Sci Transl Med, 8(336):336ra59.

17. Nadeem A, Sanborn J, Gettel DL, Ho JCS, Rydström A, Ngassam VN, Klausen TK, Pedersen SF, Lam M, Parikh AN and Svanborg C (2015). Protein receptor-independent plasma membrane remodeling by HAMLET; a tumoricidal protein-lipid complex. Sci Rep, 5:16432.

18. Ho JCS*, Nadeem A*, Rydström A, Puthia M and Svanborg C (2015). Targeting of nucleotide-binding proteins by HAMLET - a conserved tumor cell death mechanism. Oncogene, 35(7):897-907. *Equal contribution

19. Ho JCS, Sielaff H, Nadeem A, Svanborg C and Gruber G. The molecular motor F-ATP synthase is targeted by the tumoricidal protein HAMLET (2015). J Mol Biol, 427(10):1866-74.

20. Puthia M, Storm P, Nadeem A, Hsiung S, Svanborg C. Prevention and treatment of colon cancer by peroral administration of HAMLET (human α-lactalbumin made lethal to tumour cells) (2013). Gut, 63(1): 131-142.

21. Lutay N, Ambite I, Grönberg-Hernandez J, Rydström G, Ragnarsdottir B, Puthia M, Nadeem A, Zhang, J, Storm, P, Dobrindt U, Wullt, B and Svanborg C (2013). Bacterial control of host gene expression through RNA polymerase II. J Clin Invest, 123(6):2366-79.

22. Nadeem A, Syed Q, Baig S, Irfan M and Nadeem M (2010). Enhanced Production of Citric Acid by Aspergillus niger M-101 using Lower Alcohols. Turk J Biochem. 35 (1): 7-13.

Review papers, editorial & book chapter

1. Schmidtchen A, Mirza H, van der Plas MJA, Nadeem A, Puthia M, (2022). Editorial: Methods and applications in inflammation pharmacology.
Front Pharmacol, doi.org/10.3389/fphar.2022.1108263.

2. Zlatkov N, Nadeem A, Uhlin BE, Wai SN. Eco-Evolutionary Feedbacks Mediated by Bacterial Membrane Vesicles (2020).
FEMS Microbiol Rev, 45(2):fuaa047.

3. Nadeem A, Oscarsson J, Wai SN. Delivery of virulence factors by bacterial membrane vesicles to mammalian host cells (2020).  p 131-158. ISBN: 978-3-030-36330-7.

4. Ho JCS*, Nadeem A*, Svanborg C. HAMLET – A protein-lipid complex with broad tumoricidal activity (2017). Biochem Biophys Res Commun. 482(3):454-458. *Equal contribution

5. Ho JCS, Rydström A, Trulsson M, Bålfors J, Storm P, Puthia M, Nadeem A, Svanborg C. HAMLET: functional properties and therapeutic potential. (2012). Future Oncol, 8(10):1301-13.

6. Godaly G, Ambite I, Puthia M, Nadeem A, Ho J, Nagy K, Huang Y, Rydström G, Svanborg C (2016). Urinary Tract Infection Molecular Mechanisms and Clinical Translation. Pathogens, 24;5(1):24.

Patents

1. Nadeem A, Svanborg C and Ho JCS (2020). US Patent App. 16/612,272

2. Svanborg C, Nadeem A, Mok KH and Ho JCS (2018). Therapeutically active complexes. International Publication Number: WO2018/116165 A3.

3. Wai SN, Uhlin BE, Nadeem A, Persson K (2019). Vibrio cholerae protein for use against cancer. PCT/SE2020/050968

Read more on my lab website: https://sites.google.com/view/nadeemlab/home