Migration and Polysialylation

Elaine Gersz

ChemBio Spotlight #2

Paper: Polysialylation Controls Dendritic Cell Trafficking by Regulation Chemokine Recognition

http://science.sciencemag.org/content/351/6269/186

Polysialic acid (PolySia) has been shown to foster cancer progression and metastasis, but no mechanism has been elucidated. PolySia is a monosaccharide that is added post-transnationally to N/O linked glycan’s through the action of enzymes, ST8IV/II. It is also known to regulate the control of cell-cell and cell-matrix interactions controlling neuronal development and has been preliminarily shown to effect immune function. Recently, Kiermaier et al. (Science 2016;351:186-190) have tied these loose ends together showing how PolySia controls dendritic trafficking through chemokine regulation.

PolySia deficient mice display reduced cellularity of lymph nodes (LN) and a reduced LN mediated inflammatory response indicating a role for PolySia in regulating trafficking to LN’s. Immunoprecipitation reveled PolySia was present only on the surface of Dendritic Cells (DC), the antigen presenting immune cells. Further trafficking studies reveled PolySia -/- DC’s fail to migrate into the LN, even when injected into PolySia capable mice, indicating that the phenotype was cell autonomous.

Normally, CCR7 binds to chemokine’s (CCL19 or CCL21) to traffic DC’s into LN’s, however, in PolySia -/- conditions DC’s only respond to CCL19 activation not CCL21. Since CCL21 contains a known glycan binding, unstructured positive C-terminus domain it was likely that this was binding the negative PolySia. However, upon immunoprecipitation in both human and mouse cells it was determined that only CCR7 was polysialylated through both N/O type linkages not CCL21. NMR shift analysis then revealed that the CCL21 C-terminus acts in an auto-inhibitory manner inactivating its own chemokine domain, which is released by PolySia bound CCR7. This novel model of glycosylation-mediated release of chemokine auto-inhibition may also apply to other chemokine’s with similar c-terminus domains. In addition, since CCR7 is known to promote tumor metastasis this may explain the similar relationship observed with PolySia and its role in cancer progression and metasisis.

 

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PolySia deficient DC’s fail to migrate in response to CCL21 signaling (bottom right).

Response to CCL19 signaling is intact (top right).

10 Replies to “Migration and Polysialylation”

  1. Elaine,
    Really interesting article. I thought it was fascinating how the immune system’s lymph nodes and nervous system’s dendritic cells were connected through the chemokine activity and regulation. To think that a simple post-translational modification of adding a monosaccharide is somehow connected to cancer is quite unbelievable. It was also kind of fun to see different methods of experimentation in this article that I learned about in BCM 341.

    I do wonder though, if the metabolism surrounding polysialic acid is connected to this phenomenon these authors have uncovered. Is this monosaccharide something humans need to ingest more often to assist in this cell trafficking in order to avoid cancer? Great job!

    1. Interesting thought regarding the role of human consumption in this process. However, I do not think that this would be a viable target for the control of this pathway. Polysialic acid is typically produced through a pathway which involves the condensation of PEP with either ManNAc-6-P or Man-6-P which are derived from glucose. It is unlikely that by consuming excess glucose we would be able to favorable manipulate this pathway to produce more sialic acid (not to mention the known consequences of excess glucose consumption on metabolism). This chapter provides a great review of the mechanisms of biosynthesis of sialic acid.

      Varki, A., and Schauer, R. (2009). Sialic Acids. In Essentials of Glycobiology, A. Varki, R.D. Cummings, J.D. Esko, H.H. Freeze, P. Stanley, C.R. Bertozzi, G.W. Hart, and M.E. Etzler, eds. (Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press). http://www.ncbi.nlm.nih.gov/books/NBK1920/

  2. This is a very interesting study! I am curious about other chemokines similar to CCL21 (in terms of the auto-inhibition of the c-terminus). You mentioned that this type of release could be possible in other chemokines with similar c-terminus domains, but the only chemokines focused on in this study were CCL19 and CCL21. Did this paper direct you to any other resources regarding these types of chemokines? If so, do other proteins of this type have a similar role when it comes to the binding of Polysialic acid or even a similar mechanism for auto-inhibition?

    1. Great thought! The authors focus on CCL19 and CCL21 in this study since they have been shown in previous research to promote this type of dendritic cellular trafficking. Your question is one I believe that the authors are proposing as a topic for future research. Since it is seen in this specific chemokine it may be applicable to others as well, however the research on this has yet to be conducted.

      Since primary structures of chemokines have been identified alignments such as the one seen here (http://imgur.com/a1ExWeG) [Fernandez 2002] can be constructed to visualize which chemokines which have extended C-terminus domains indicating they may have a similar auto-inhibition mechanism, this includes CCL16, CCL24, CCL25 and CCL27.

      Fernandez, E. J. & Lolis, E. Structure,function, and Inhibition of Chemokines. Annual Review of Pharmacology & Toxicology 42, 469 (2002).

  3. I really enjoyed your blog post, Elaine! It got me thinking about cancer progression and metastasis related to PolySia and how it could possibly be inhibited to stop further progression and metastasis. Did the authors give any indication of a further study in which this would be addressed?

    Just to clarify, is PolySia bound CCR7 causing to inactivation of CCL21, and if so, is there a way to prevent this binding? This way CCL21 can stay active and bind to CCR7 instead, so there can be movement of dendritic cells into lymph nodes?

    1. I’m glad you found it interesting! I am always fascinated by how many mechanisms cells use to perform their day to day function and how many of these mechanisms we have yet to fully comprehend.

      In regards to your point of clarification, Polysia is attached to CCR7. The interactions between this polysia and CCL21 cause the c-terminus of CCL21 to be released from interactions with itself thereby activating CCL21 which normally is found inactive. So polysia is actually the activating agent in this case.

      The authors did not indicate any specific methods or experiments they plan to conduct to further investigate their findings for a potential theraputic application. However, I would propose one method would be to target the polysia transferase (ST8Sia IV) which is responsible for the attachment of polysia to CCR7. This would limit the movement of skin dendritic cells to the lymph nodes. This would serve to prevent metastasis skin cancer cells to lymph nodes and could serve as a treatment for patients with primary skin cancer.

  4. Thanks for finding this great study Elaine. It seems polysialylation of CCR7 affects the activity of chemokines, specifically by relieving auto-inhibited ones. I am interested that the authors explore the relationship between polysialylation and the activity of chemokines because many viruses exploit sialic acid on cell surfaces for binding and invasion. Have you come across any other functions of polysialylation or sialic acid in regulating the immune system?

    1. Great point Elliot! This is the first study to indicate a auto-inhibitory role in chemokines, however, it may have a broader basis then in CCL21 alone as many other chemokines have extended C-termini (You see my reply to Tyler’s question for a more detailed response on which ones) .

      Sialic acid plays a huge role in our immune function in regards to pathogens such as bacteria and viruses. Sialic acid found on cell surfaces can act as a ligand for pathogens indicating they have found a new host. Bacteria posses sialidases which remove sialic acids from glycan chains, some species use the free sialic acid as a energy source. Others use the sialic acid to decorate their own cell wall glycans to avert immune response. Interestingly, bacteria make their own sialic acid. However, as a result of convergent evolution, they possess different enzymes then mammals do.

      A great review of the role of sialic acid in immunity can be found here;

      Varki, A. & Gagneux, P. Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci 1253, 16–36 (2012). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357316/

  5. Great Article and the blogpost was very helpful. I found it very interesting that the authors created a CCL19 chimera with a transplanted CCL21 c-terminus to increase CCL19 sensitivity to PolySia by CCR7 in order to show that the c-terminus of CCL21 was responsible for polysialation and subsequent activation. The authors also indicate that CCR7 is involved in metastatic tumors, in respect to
    potential therapeutic research, do the authors emphasize further research in CCR7 ‘s role in Polysialation or the c-terminus of CCL21?

    1. I thought their technique of using a chimeric chemokine was very scientifically sound. It provided concrete evidence of the c-terminus’s role in inhibition. The authors are not specific in their own future intentions, perhaps they are already working and do not want another scientist to beat them to a future discovery!

      However, I believe that both serve as viable therapeutic targets. As I explained in my response to Nicole above, targeting of the the polysia transferase seems like a good candidate as it provides specificity to certain cell types. However, a small molecule drug target could also be designed to bind and hold to c-terminus of CCL21 to itself to lock the molecule into an inhibitory state providing another potential mechanism of therapeutic control.

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