WASF, CDC42, MTOC, and cytoskeleton dysfunction in ME?

Research in gene expression and proteomic data has identified a list of 11 genes which may play important roles in ME/CFS. These genes revolve around the actin and microtubule cytoskeleton (1).

Two genes that caught my eye were WASF3 (also known as WAVE3) and TNK2

WASF

Wiskott-Aldrich syndrome protein family member 3 (WASF3) is a protein that forms a multiprotein complex that links receptor kinases and actin. That means WASF3 regulates the actin cytoskeleton.

Wiskott-Aldrich syndrome protein (WASP) was the first identified number of the family. It is required for immune cell functions, in fx. NK cells and CD4⁺CD25⁺FOXP3⁺ regulatory T cells.

Loss of WASP activity leads to Wiskott-Aldrich syndrome involving immunodeficiency and autoimmunity. WAS patients has severe NK cell functional impairments. Inadequate immune responsiveness to Epstein-Barr Virus is observed (2) (I recommend Figure 3 page 188 in Ref 2)

CDC42

CDC42 (cell division control Protein 42 homolog) activates multiple pathways involved in cell polarity accomplished by reorganisation of the actin and microtubule cytoskeleton.

Examples of pathways:

• CDC42 -> WASP -> Arp2/3 -> polarized actin cytoskeleton
• CDC42 -> PAKs -> Stathmin -> polarized microtubule cytoskeleton

(I recommend Figure 4 page 1297 Ref 3)

These processes are essential for the function of the MTOC (3)

MTOC

The MTOC (microtubule organizing center) function is played by the centrosome, which contains centrioles and PCM (pericentriolor material).

The MTOCs are present in all eukaryotic cells. It is commonly known that MTOC is responsible for the formation of the mitotic and meiotic spindle apparatus during cell division. But MTOC is involved in many processes, fx. in the immunological response (4)

WASF, CDC42, and MTOC in NK cells

Formation of the immunological synapse (IS) between NK cells and target cells is dependent of WASF, CDC42 and MTOC.

Polarization of the MTOC and lytic granules to the IS is required for NK cell cytotoxicity. (I recommend Figure 1 page 247 in ref 5).

WASP appears to be the predominantly utilized family member in NK cells.

Both WASP and WAVE2 are expressed in T and NK cells (5)

ME hypothesis

WASF, CDC42, MTOC and the cytoskeleton are involved in ME immune dysfunction.

The cytoskeleton and regulating proteins are target to autoantibodies in several autoimmune diseases.

Do we have autoantibodies against proteins in the WASF - CDC42 - MTOC pathway in ME?

References:

1. Pihur et al. Bioinformation 6 (3):120-124 (2011). Meta analysis of Chronic Fatigue Syndrome through integration of clinical expression SNP and proteomic data.
2. Thrasher and Burns. WASP: a key immunological multitasker. Nature Reviews, March 2010, volumen 10.doi:10.1038/nri2724
3. Etienne-Manneville CDC42 - the centre of polarity. Journal of Cell Science 117, 1291-1300
4. Kloc et al. The newly found functions of MTOC in immunological response. Journal of Leucocyte Biology, volumen 95, March 2014. doi:10.1189/jib.0813468
5. Mace et al. Cell biological steps and checkpoints in accessing NK cell cytotoxicity. Immunology and Cell Biology (2014) 92, doi:10.1038/ccb.2013.96