The Essential Role of anxA2 in Langerhans Cell Birbeck Granules Formation

Abstract

Langerhans cells (LC) are the resident antigen presenting cells of the mucosal epithelium and play an essential role in initiating immune responses. LC are the only cells in the body to contain Birbeck granules (BG), which are unique cytoplasmic organelles comprised of c-type lectin langerin. Studies of BG have historically focused on morphological characterizations, but BG have also been implicated in viral antigen processing which suggests that they can serve a function in antiviral immunity. This study focused on investigating proteins that could be involved in BG formation to further characterize their structure using transmission electron microscopy (TEM). Here, we report a critical role for the protein annexin A2 (anxA2) in the proper formation of BG structures. When anxA2 expression is downregulated, langerin expression decreases, cytoplasmic BG are nearly ablated, and the presence of malformed BG-like structures increases. Furthermore, in the absence of anxA2, we found langerin was no longer localized to BG or BG-like structures. Taken together, these results indicate an essential role for anxA2 in facilitating the proper formation of BG.

Cryo-electron tomography of Birbeck granules reveals the molecular mechanism of langerin lattice formation

“…The formation of clathrin pits may also be involved in membrane invagination, because the cytoplasmic ends of Birbeck granules are coated with clathrin (Mc et al, 2002). Additionally, it is possible that other intracellular mechanisms such as the actin cytoskeleton, are involved in this membrane deformation process because annexin A2 is required for the proper formation of Birbeck granules (Thornton et al, 2020).…”

“…Additionally, it is possible that other intracellular mechanisms such as the actin cytoskeleton, are involved in this membrane deformation process because annexin A2 is required for the proper formation of Birbeck granules (Thornton et al, 2020).…”

Annexin A2: The diversity of pathological effects in tumorigenesis and immune response

“…16,148 Birbeck granules (BG) located in the antigen presenting cell Langerhans cells (LC) is a unique cytoplasmic organelle and plays a vital role in initiating an immune response. 149 By knocking down ANXA2 by shRNA lentiviral transfection in human acute myeloid leukemia cell line MUTZ-3 (RRID:CVCL_ 1433), the langerin expression was decreased, and cytoplasmic BG was nearly ablated. The study suggested ANXA2 played a vital role in facilitating the correct formation of BG and initiating the adaptive immune response.…”

“…The study suggested ANXA2 played a vital role in facilitating the correct formation of BG and initiating the adaptive immune response. 149 ANXA2 is also implicated in the regulation of lung function in response to viral infections. In severe cases of coronavirus disease 2019 (COVID-19), high levels of activated B cells were observed.…”

Special Issue “Recent Developments in Annexin Biology”

“…Several of the studies described in this Special Issue focus on uncovering the cellular roles of annexins, and illustrate the unique involvement of annexins in cellular homeostasis and stress. A homeostatic role of annexin that is examined by Thornton et al [1] identifies the requirement of intracellular Annexin A2 (AnxA2) in supporting the biogenesis of the Birbeck granule, a specialized compartment found in the Langerhans cells. In contrast, Gabel et al [2] focus on the extracellular release of AnxA2 by way of secretory granule fusion in the neuroendocrine cells, which results in AnxA2 becoming detectable at the extracellular surface.…”