bims-actimu Biomed News
on Actinopathies in inborn errors of immunity
Issue of 2023‒10‒01
six papers selected by
Elodie Busch, University of Strasbourg

  1. Pathol Res Pract. 2023 Sep 22. pii: S0344-0338(23)00529-0. [Epub ahead of print]250 154829
      Melanoma is an aggressive tumor with a poor prognosis that worsens in the metastatic phase. Distruptions of epigenetic mechanisms is known to effect cancer stem cells (CSCs) activity. Malignant melanoma (MM) progression may be promoted by changes in the genetic structure of CSC. Thus, treatments that target epigenetic modifications could be a promising weapon, especially in melanoma. Here, we compared p300, HDAC9, and F-actin proteins in melanoma CSCs (CD133+), non-CSCs (CD133-) and CHL-1 cell line, as well as cell migration and division rates. At 4 and 6 h, P300 protein levels in CHL-1 and CD133 + were remarkably similar, and the CD133- showed increases in expression levels as the incubation period lengthened. HDAC9 protein intensity decreased in CHL-1, increased in the CD133-, and remained relatively unchanged in the CD133+ as the incubation period lengthened. The mean value of F-actin expression level increased in all cell group with time, when the highest increase observed in CHL-1. In conclusion, our studies contribute to the management of metastatic diseases in the future and offer new insight into the molecular basis of the initiation and progression of MM.
    Keywords:  Cancer stem cell; F-actin; HDAC9; Malignant melanoma; Migration; P300
  2. bioRxiv. 2023 Sep 13. pii: 2023.09.13.557508. [Epub ahead of print]
      The assembly and disassembly of actin filaments and their regulatory proteins are crucial for maintaining cell structure or changing physiological state. However, because of the tremendous global impact of actin on diverse cellular processes, dissecting the specific role of actin regulatory proteins remains challenging. In this study, we employ actin waves that propagate on the cortex of mast cell to investigate the interplay between formins and the Arp2/3 complex in the nucleating and turnover of cortical actin. Our findings reveal that the recruitment of FMNL1 and mDia3 precedes the Arp2/3 complex in cortical actin waves. Membrane and GTPase-interaction can drive oscillations of FMNL1 in an actin-dependent manner, but active Cdc42 waves or constitutively-active FMNL1 mutant can form without actin waves. In addition to the apparent coordinated assembly of formins and Arp2/3, we further reveal their antagonism, where inhibition of Arp2/3 complex by CK-666 led to a transient increase in the recruitment of formins and actin polymerization. Our analysis suggest that the antagonism could not be explained for the competition between FMNL1 and Arp2/3 for monomeric actin. Rather, it is regulated by a limited pool of their common upstream regulator, Cdc42, whose level is negatively regulated by Arp2/3. Collectively, our study highlights the multifaceted interactions, cooperative or competitive, between formins and Arp2/3 complex, in the intricate and dynamic control of actin cytoskeletal network.
  3. J Cell Sci. 2023 09 15. pii: jcs260985. [Epub ahead of print]136(18):
      Shear stress is essential for normal physiology and malignancy. Common physiological processes - such as blood flow, particle flow in the gut, or contact between migratory cell clusters and their substrate - produce shear stress that can have an impact on the behavior of different tissues. In addition, shear stress has roles in processes of biomedical interest, such as wound healing, cancer and fibrosis induced by soft implants. Thus, understanding how cells react and adapt to shear stress is important. In this Review, we discuss in vivo and in vitro data obtained from vascular and epithelial models; highlight the insights these have afforded regarding the general mechanisms through which cells sense, transduce and respond to shear stress at the cellular levels; and outline how the changes cells experience in response to shear stress impact tissue organization. Finally, we discuss the role of shear stress in collective cell migration, which is only starting to be appreciated. We review our current understanding of the effects of shear stress in the context of embryo development, cancer and fibrosis, and invite the scientific community to further investigate the role of shear stress in these scenarios.
    Keywords:  Biomechanics; Cytoskeleton; Fluid shear stress; Shear stress
  4. Nat Cell Biol. 2023 Sep 28.
      Integrin-mediated focal adhesions are the primary architectures that transmit forces between the extracellular matrix (ECM) and the actin cytoskeleton. Although focal adhesions are abundant on rigid and flat substrates that support high mechanical tensions, they are sparse in soft three-dimensional (3D) environments. Here we report curvature-dependent integrin-mediated adhesions called curved adhesions. Their formation is regulated by the membrane curvatures imposed by the topography of ECM protein fibres. Curved adhesions are mediated by integrin ɑvβ5 and are molecularly distinct from focal adhesions and clathrin lattices. The molecular mechanism involves a previously unknown interaction between integrin β5 and a curvature-sensing protein, FCHo2. We find that curved adhesions are prevalent in physiological conditions, and disruption of curved adhesions inhibits the migration of some cancer cell lines in 3D fibre matrices. These findings provide a mechanism for cell anchorage to natural protein fibres and suggest that curved adhesions may serve as a potential therapeutic target.
  5. J Membr Biol. 2023 Sep 29.
      Flow is an important physiological signal and modulates a variety of cell functions. However, the molecular mechanisms that cells use to sense flow have remained surprisingly opaque. The first steps in flow sensing are likely to occur at the plasma membrane, the fluid barrier between the inside and outside of a cell. This membrane is an organized, two-dimensional molecular array that has both solid and fluid properties. The mobility of membrane proteins and lipids is constrained by complex interactions with the cytoskeletal protein network that supports the membrane. Physiologically relevant flows can only generate tiny forces on individual proteins, smaller than those from thermal noise. However, cells could overcome this problem by sensing micron-scale concentration gradients of extracellular membrane proteins. This is possible in cell plasma membranes because their particular physical state allows flow to sort membrane proteins laterally over the extracellular surface.
    Keywords:  Endothelial cell; Flow mechanosensing; Membrane biophysics; Microfluidics; Shear stress; Supported lipid bilayer
  6. Nat Struct Mol Biol. 2023 Sep 25.
      The release of inorganic phosphate (Pi) from actin filaments constitutes a key step in their regulated turnover, which is fundamental to many cellular functions. The mechanisms underlying Pi release from the core and barbed end of actin filaments remain unclear. Here, using human and bovine actin isoforms, we combine cryo-EM with molecular-dynamics simulations and in vitro reconstitution to demonstrate how actin releases Pi through a 'molecular backdoor'. While constantly open at the barbed end, the backdoor is predominantly closed in filament-core subunits and opens only transiently through concerted amino acid rearrangements. This explains why Pi escapes rapidly from the filament end but slowly from internal subunits. In a nemaline-myopathy-associated actin variant, the backdoor is predominantly open in filament-core subunits, resulting in accelerated Pi release and filaments with drastically shortened ADP-Pi caps. Our results provide the molecular basis for Pi release from actin and exemplify how a disease-linked mutation distorts the nucleotide-state distribution and atomic structure of the filament.