TBC1D10C is a cytoskeletal functional linker that modulates cell spreading and phagocytosis in macrophages

Abstract

Cell spreading and phagocytosis are notably regulated by small GTPases and GAP proteins. TBC1D10C is a dual inhibitory protein with GAP activity. In immune cells, TBC1D10C is one of the elements regulating lymphocyte activation. However, its specific role in macrophages remains unknown. Here, we show that TBC1D10C engages in functions dependent on the cytoskeleton and plasma membrane reorganization. Using ex vivo and in vitro assays, we found that elimination and overexpression of TBC1D10C modified the cytoskeletal architecture of macrophages by decreasing and increasing the spreading ability of these cells, respectively. In addition, TBC1D10C overexpression contributed to higher phagocytic activity against Burkholderia cenocepacia and to increased cell membrane tension. Furthermore, by performing in vitro and in silico analyses, we identified 27 TBC1D10C-interacting proteins, some of which were functionally classified as protein complexes involved in cytoskeletal dynamics. Interestingly, we identified one unreported TBC1D10C-intrinsically disordered region (IDR) with biological potential at the cytoskeleton level. Our results demonstrate that TBC1D10C shapes macrophage activity by inducing reorganization of the cytoskeleton-plasma membrane in cell spreading and phagocytosis. We anticipate our results will be the basis for further studies focused on TBC1D10C. For example, the specific molecular mechanism in Burkholderia cenocepacia phagocytosis and functional analysis of TBC1D10C-IDR are needed to further understand its role in health and disease.

PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

“…DENND1C (DENN domain containing 1C) is a GEF activating Rab35 that regulates actin cytoskeleton [ 111 ]. TBC1D10C (TBC domain family member 10C) is a Ras GTPase-activating protein (GAP) and an inhibitor of Ras and calcineurin [ 112 ]; its role in regulating macrophage’s cytoskeleton [ 113 ] supports its association with immune escape observed in this study. TBC1D9 (another member of the family and a potential GAP) is a component gene of Overlap36 (Table 4 ), indicating the importance of this family in melanoma immune evasion.…”

The expression and prognostic role of sphingosine 1-phosphate receptor 4 (S1PR4) as a biomarker in skin cutaneous melanoma

“…TBC1D10C de ciency can increase the number and cytotoxic activity of CD8 + T cells, without affecting CD4 + T cells. On the other hand [17],…”

Integrative ATAC‐seq and RNA‐seq analysis associated with diabetic nephropathy and identification of novel targets for treatment by dapagliflozin

“…Our finding suggests that DAPA may regulate the balance of UGT enzymes in db/db mouse model to improve diabetes. Other genes such as Lrrc8d (involved in maintaining cellular glucose homeostasis), 28 Ptprn2 (involved in the cellular response to glucose stimulus), 29,30 Arntl (linked to gluconeogenesis and lipogenesis), 31 Tmem171 (an integral component of membrane), 32 Col19a1 (involved in extracellular matrix remodeling), 33,34 Dock2 (GTPase activator involved in T cell activation and immunological synapse formation) 34 and Tbc1d10c (another GTPase activator connected with negative regulation of B cell activation), 35,36 highlighted the importance of glucolipid metabolism and immune balance in DN and DAPA treatment process.…”