MARCKS-related protein regulates cytoskeletal organization at cell–cell and cell–substrate contacts in epithelial cells

Abstract

Treatment of epithelial cells with interferon-γ and TNF-α (IFN/TNF) results in increased paracellular permeability. To identify relevant proteins mediating barrier disruption, we performed proximity-dependent biotinylation (BioID) of occludin and found that tagging of MARCKS-related protein (MRP; also known as MARCKSL1) increased ∼20-fold following IFN/TNF administration. GFP-MRP was focused at the lateral cell membrane and its overexpression potentiated the physiological response of the tight junction barrier to cytokines. However, deletion of MRP did not abrogate the cytokine responses, suggesting that MRP is not required in the occludin-dependent IFN/TNF response. Instead, our results reveal a key role for MRP in epithelial cells in control of multiple actin-based structures, likely by regulation of integrin signaling. Changes in focal adhesion organization and basal actin stress fibers in MRP-knockout (KO) cells were reminiscent of those seen in FAK-KO cells. In addition, we found alterations in cell-cell interactions in MRP-KO cells associated with increased junctional tension, suggesting that MRP may play a role in focal adhesion-adherens junction cross talk. Together, our results are consistent with a key role for MRP in cytoskeletal organization of cell contacts in epithelial cells.

Plasma proteins, cognitive decline, and 20‐year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies

“…66 Increased plasma concentrations of other proteins could represent responses to pathogens (e.g., RNAS6 67,68 and HE4), 69 or be part of the increased immune response (e.g., NPS-PLA2, TREM2, MIC-1, OPG, TIMP-4, SVEP1, MARCKSL1, and CDCP1). 49,52,53,55,66,[70][71][72][73][74][75][76][77][78][79] Degeneration of the BBB provides a further potential mechanism underlying the observed protein-dementia associations. The subsequent passage of toxins and proteins into the central nervous system contributes to reduced neuronal plasticity, activation of microglia, disruptions in lipid metabolism, increased neuroinflammation, amyloid and tau accumulation, and neurodegeneration (Figure S6c).…”

Association of plasma proteins with rate of cognitive decline and dementia: 20-year follow-up of the Whitehall II and ARIC cohort studies

“…We identified two additional proteins, SVEP1 and MARCKSL1, which may also act in these processes. 36, 37 SVEP1 can also activate the complement system, which, if prolonged, can be detrimental to endothelial cells. 38 Leakage of complement through damaged endothelium into the CNS, in turn, can cause the synapse loss in the hippocampus observed in dementia.…”

Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients

“…The MARCKS family of proteins differ in subcellular location and membrane binding affinity, and includes the myristoylated alanine-rich C-kinase substrate-like 1 (MARCKSL1), also known as MARCKS-related protein (MRP) and MARCKS-like protein (MLP) [ 20 ]. MARCKSL1 is a membrane-bound actin cytoskeleton regulator [ 18 , 21 ], associated with tumorigenesis in several cancer types [ 22 , 23 ]. In breast cancer cell lines, MARCKSL1 knockdown results in decreased migration [ 24 ].…”