Rho GTPases and RhoGDIs in the Regulation of Mast Cell Degranulation

• Author / Creator

  Sheshachalam, Avinash

• Mast cells (MCs) are tissue resident innate immune cells. They are recognized for their immunoregulatory roles in the regulation of innate and adaptive immunity. Aberrant activation and responses of MCs result in inflammatory disorders like allergies. Thus, the biological pathways that control MC activation and responses are attractive targets for the treatment of MC-mediated inflammation. In this thesis, I present my data on the essential roles of Rho GTPases and their regulator, RhoGDI, during FcεRI-activation of RBL-2H3, a rat basophil leukemia cell line widely used as model MCs, and bone marrow-derived MCs (BMMCs).

  We demonstrated that Rho GTPase subfamily proteins regulate unique events during the activation of MCs. Rac drives the formation of actin rich peripheral extensions and RhoA is involved in granule trafficking via microtubule extension. Inhibition of either Rho protein by pharmacological interference, significantly prevents MC degranulation. Further, we also characterized the distinct properties of RhoGDIs in the regulation of Rho GTPases. RhoGDIs may hold the key for strategic regulation of spatial and temporal Rho signaling. Here, we showed that RhoGDI subfamily members possess distinct functional and biochemical properties in their regulation of Rho proteins. These distinctions of functions could be an evolutionary conserved feature of RhoGDIs. We found that RhoGDI2 shows distinct localization to membrane compartments. This discrete localization in MCs could result in spatial regulation of Rho GTPases, which in turn, may impact MC degranulation. Further work using reduced expression of RhoGDIs in MCs can reveal the non-redundant and essential roles of RhoGDIs during FcεRI-activation of MCs.

• Subjects / Keywords

  • Mast cells
  • Rho GTPase
  • RhoGDI
  • degranulation
  • exocytosis
  • regulation

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3R20SC57

• License

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