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Pelaseyed LaB

EXPLORING EPITHELIAL CELL INNATE IMMUNITY
AGAINST GUT MICROBES

Our intestines are home to trillions of bacteria. The interaction between bacteria and our immune system has received much attention. Yet, we know little about the role of intestinal epithelial cells that physically separate bacteria from our immune cells. Pattern recognition receptors that recognize microbial molecules are mainly non-epithelial and restricted to the lamina propria in the small intestine. Consequently, there is a critical knowledge gap on how intestinal epithelial cells sense the microbiota and how beneficial bacteria stimulate epithelial cells to establish a robust barrier.

Membrane mucins are extended surface glycoproteins that cover luminal surfaces of intestinal epithelial cells. Membrane mucins are uniquely poised to function as epithelial sensors for gut bacteria, but their function is unknown. Our aim is to elucidate the function of membrane mucins and to understand how they assist epithelial cells in establishing intestinal barrier integrity.

OUr research

Bacteria in our intestine exceed 10 trillions. In healthy individuals, an impermeable layer of secreted mucins separates bacteria from host intestinal cells.

In diseases such as Inflammatory bowel disease (IBD), bacteria breach the mucus barrier and reach epithelial cells covered with bottlebrush-like glycoproteins called transmembrane mucins. Despite the fact that transmembrane mucins extend up to 1 μm into the intestinal lumen and are ideal docking sites for penetrating bacteria, their biological function is unknown.

Our goal is to determine how transmembrane mucins sense bacteria and induce intestinal cell protection against bacterial infections. Our research is within the important and expanding research field of host-microbe interaction. Our investigation of the role of transmembrane mucins is both timely and needed.

Schematic view of transmembrane mucin dynamics in distal tips of microvilli.
A) Regulation of microvilli formation is mediated by Ezrin phosphocycling.
B) Regulation of transmembrane mucin is regulated by PDZK1.

SPECIFIC AIMS:

We have shown that trafficking of Transmembrane (TM) mucins to the apical microvilli of intestinal epithelial cells is under tight regulation (Malmberg, Pelaseyed et al., 2008; Pelaseyed and Hansson, 2011; Pelaseyed et al., 2013). However, the details of this regulatory machinery remains to be clarified. We aim to:

1. Identify a novel signaling pathway by applying a global interactome analysis of transmembrane mucins
The formation of microvilli is controlled by Ezrin phosphorylation distally in microvilli, a process that requires the phosphatidylinositol PIP2 and a local apical kinase LOK (Viswanatha et al, 2012; Pelaseyed et al., 2017). Transmembrane mucin MUC17 is tethered to the apical membrane of intestinal epithelial cells via a direct interaction with the scaffolding protein PDZK1 (Malmberg, Pelaseyed et al., 2008). In turn, PDZK1 exist in a regulated and dynamic complex together with EBP50 and Ezrin. EBP50 and PDZK1 are PDZ domain-containing proteins that tether a diverse set of membrane proteins to the plasma membrane. For example, PDZK1 interacts with the CFTR anion channel that secretes bicarbonate during intestinal mucus release. Interestingly, we discovered that secretory stimulus that mobilizes CFTR at apical surfaces, simultaneously removes TM mucin MUC17 from the same surfaces (Pelaseyed et al., 2013). This indicates that TM mucin trafficking is intimately associated with intestinal flushing and clearance of intestinal bacteria. We will apply a global interactome analysis of MUC17 in order to identify downstream singling components that promote intestinal epithelial cell protection.

2. Determine how transmembrane mucin communicate with epithelial innate immune system
Gut microbes produce proteases in order to penetrate down to intestinal epithelial cells, and then deploy adhesins as well as a second set of proteases to attach to and degrade transmembrane mucins. We have identified several commensal and pathogenic microbes that bind and degrade transmembrane mucins. We now aim to determine the fate of transmembrane mucins that are affected by bacterial factors. We believe that transmembrane mucins help sense the gut microbiota in order to trigger epithelial cell innate immune response against the gut microbiota. 

MAJOr Funding:

Swedish Society for Medical Research
Wenner-Gren Foundations
Sahlgrenska Academy

PUBLICATions

1: Pelaseyed T, Bretscher A. Regulation of actin-based apical structures on epithelial cells. J Cell Sci. 2018 Oct 17;131(20). pii: jcs221853. doi:10.1242/jcs.221853. Review. PubMed PMID: 30333133.

2: Schneider H, Pelaseyed T, Svensson F, Johansson MEV. Study of mucin turnover in the small intestine by in vivo labeling. Sci Rep. 2018 Apr 10;8(1):5760. doi:10.1038/s41598-018-24148-x. PubMed PMID: 29636525; PubMed Central PMCID:PMC5893601.

3: Pelaseyed T, Viswanatha R, Sauvanet C, Filter JJ, Goldberg ML, Bretscher A. Ezrin activation by LOK phosphorylation involves a PIP(2)-dependent wedge mechanism. Elife. 2017 Apr 21;6. pii: e22759. doi: 10.7554/eLife.22759. PubMed PMID: 28430576; PubMed Central PMCID: PMC5400502.

4: Lebrero-Fernández C, Bergström JH, Pelaseyed T, Bas-Forsberg A. Murine Butyrophilin-Like 1 and Btnl6 Form Heteromeric Complexes in Small Intestinal Epithelial Cells and Promote Proliferation of Local T Lymphocytes. Front Immunol. 2016 Jan 19;7:1. doi: 10.3389/fimmu.2016.00001. eCollection 2016. PubMed PMID: 26834743; PubMed Central PMCID: PMC4717187.

5: Sauvanet C, Wayt J, Pelaseyed T, Bretscher A. Structure, regulation, and functional diversity of microvilli on the apical domain of epithelial cells. Annu Rev Cell Dev Biol. 2015;31:593-621. doi: 10.1146/annurev-cellbio-100814-125234. Review. PubMed PMID: 26566117.

6: Pelaseyed T, Bergström JH, Gustafsson JK, Ermund A, Birchenough GM, Schütte A, van der Post S, Svensson F, Rodríguez-Piñeiro AM, Nyström EE, Wising C, Johansson ME, Hansson GC. The mucus and mucins of the goblet cells and enterocytes provide  the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014 Jul;260(1):8-20. doi: 10.1111/imr.12182. Review. PubMed PMID: 24942678; PubMed Central PMCID: PMC4281373.

7: Pelaseyed T, Gustafsson JK, Gustafsson IJ, Ermund A, Hansson GC. Carbachol-induced MUC17 endocytosis is concomitant with NHE3 internalization and CFTR membrane recruitment in enterocytes. Am J Physiol Cell Physiol. 2013 Aug 15;305(4):C457-67. doi: 10.1152/ajpcell.00141.2013. Epub 2013 Jun 19. PubMed PMID: 23784542; PubMed Central PMCID: PMC3891215.

8: Pelaseyed T, Zäch M, Petersson AC, Svensson F, Johansson DG, Hansson GC. Unfolding dynamics of the mucin SEA domain probed by force spectroscopy suggest that it acts as a cell-protective device. FEBS J. 2013 Mar;280(6):1491-501. doi: 10.1111/febs.12144. Epub 2013 Feb 21. PubMed PMID: 23331320; PubMed Central PMCID: PMC3746175.

9: Johansson ME, Ambort D, Pelaseyed T, Schütte A, Gustafsson JK, Ermund A, Subramani DB, Holmén-Larsson JM, Thomsson KA, Bergström JH, van der Post S, Rodriguez-Piñeiro AM, Sjövall H, Bäckström M, Hansson GC. Composition and functional role of the mucus layers in the intestine. Cell Mol Life Sci. 2011 Nov;68(22):3635-41. doi: 10.1007/s00018-011-0822-3. Epub 2011 Sep 25. Review.
PubMed PMID: 21947475.

10: Pelaseyed T, Hansson GC. CFTR anion channel modulates expression of human transmembrane mucin MUC3 through the PDZ protein GOPC. J Cell Sci. 2011 Sep 15;124(Pt 18):3074-83. doi: 10.1242/jcs.076943. Epub 2011 Aug 18. PubMed PMID: 21852426.

11: Malmberg EK, Pelaseyed T, Petersson AC, Seidler UE, De Jonge H, Riordan JR, Hansson GC. The C-terminus of the transmembrane mucin MUC17 binds to the scaffold protein PDZK1 that stably localizes it to the enterocyte apical membrane in the small intestine. Biochem J. 2008 Mar 1;410(2):283-9. PubMed PMID: 17990980.

See complete list of publications on Pubmed.

Grants & Awards


Active research grants as Principal Investigator

Swedish Society for Medical Research, Start grant #S17-0005 (2018-2022) (success rate 6%)
Sahlgrenska Academy PhD Training Grant #U2018/162 (2019-2022)
NIH/NIAID/MIST Scholar Award in Mucosal Immunity (2018-2019)
The Wenner-Gren Foundations, Starting grant #FT2017-0002 (2017-2019)
The Wenner-Gren Foundations, International Postdoc Training grant, #UPD2018-0065 (2019-2020)
The Wenner-Gren Foundations, International Postdoc Training grant, #WUP2017-0005 (2018-2019)
Åke Wiberg's Foundation, Research grant, #M17-0062 (2018-2019)
The Jeansson Foundations, Startup grant #JS2017-0003 (2018-2019)

Institutional support

Sahlgrenska Academy co-funding of SSMF Large Grant, #E2018/611 (2018-2022)

Completed research grants

Sahlgrenska Academy International Starting Grant, #E2015/521 (2015)
Wilhem and Martina Lundgren’s Foundation, #2017-1655 (2017-2018)
Wenner-Gren Postdoctoral Fellowship (2014-2017) (success rate 5%)
The Swedish Cystic Fibrosis Association’s Postdoctoral stipend (2014)
Birgit and Hellmuth Hertz Foundation’s Postdoctoral scholarship (2013)

Awards

Wilhelm and Martina Lundgren’s Foundation (2006-2012)
European CF Young Investigators meeting, Lille, France (2008) * 1st prize for the best oral presentation
The Swedish Cystic Fibrosis Association’s scholarship (2006-2009)

 

Our Team

The Pelaseyed Lab consists of a team of devoted researches. We are undergraduates, graduates, postdocs and senior researchers.

 
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Thaher Pelaseyed, PhD

Thaher Pelaseyed is a Assistant Professor in Department of Medical Biochemistry and Cell Biology at University of Gothenburg. After graduating with a Masters degree in Pharmaceutical Bioscience (2006), Thaher did his graduate study at University of Gothenburg, receiving a PhD in Medical Biochemistry (2012). He then did his postdoctoral work as a Wenner-Gren Postdoctoral Fellow at Cornell University where he studied the morphological regulation of apical membrane domains in epithelial cells. He returned to University of Gothenburg and Institute of Biomedicine in 2016.

Read his full CV here.

 
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Sofia Jäverfelt
PhD Student

Sofia is a MSc in Pharmacy from University of Gothenburg, Sweden. Sofia is using mass spectrometry to study the dynamic interactome of intestinal transmembrane mucins.

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ELENA Layunta HerNÁNdez, POstdoctoral associate

Elena has a PhD in Biomedical and Biotechnological Sciences from University of Zaragoza, Spain. Elena works on the crosstalk between gut microbiota and host epithelial cells in regulation of transmembrane mucins.

 
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Anandi Rajan
Postdoc

Anandi has a PhD in Virology from Umeå University, Sweden. Anandi is focusing on identifying microbial proteins that interact with and process intestinal transmembrane mucins.

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Gustaf Hellsén
STUDENT

Gustaf is an undergraduate medical student at University of Gothenburg. Gustaf is working on conformational changes that occur in transmembrane mucins upon bacterial interactions.

careers

Open positions:

We are always looking for motivated young researcher who want to investigate host epithelial defense system. We offer a number of exciting projects associated with clarifying the fundamental function of intestinal transmembrane mucins. Current projects include,

Project 1: To identify bacteria that interact with transmembrane mucins. To determine the mode of interaction between bacteria and transmembrane mucins. To determine how bacterial interactions affects the biochemistry of transmembrane mucins.

Project 2: To identify the interactome of intestinal transmembrane mucins. To determine how different interacting partners affect transmembrane mucin synthesis and biology in intestinal epithelial cells.

Project 3: To determine the dynamics of transmembrane mucin in apical aspects of intestinal epithelial cells. To determine proteins components of the transmembrane mucin trafficking and recycling machinery. To determine how bacterial binding affects transmembrane mucin trafficking and recycling at apical membrane domains. 

Project 4: To determine the function of the extracellular SEA domain of intestinal transmembrane mucins.

 

Contact Us

We welcome enthusiastic and independently-minded postdocs as well as graduate and undergraduate students.

Applicants should email Thaher Pelaseyed with a cover letter, CV + bibliography and three letters of recommendation.

Thaher Pelaseyed, PhD
Institute of Biomedicine
Department of Medical Biochemistry and Cell Biology
University of Gothenburg
SWEDEN

Office: +46 (0) 31-7863046
Cell: +46(0)733-79 43 47
thaher.pelaseyed@medkem.gu.se

Visit: Medicinaregatan 9A, 413 90 Gothenburg, Sweden
Mail: Box 440, 405 30 Gothenburg, Sweden