A MEC-2/stomatin condensate liquid-to-solid phase transition controls neuronal mechanotransduction during touch sensing

Abstract

A growing body of work suggests that the material properties of biomolecular condensates ensuing from liquid–liquid phase separation change with time. How this aging process is controlled and whether the condensates with distinct material properties can have different biological functions is currently unknown. Using Caenorhabditis elegans as a model, we show that MEC-2/stomatin undergoes a rigidity phase transition from fluid-like to solid-like condensates that facilitate transport and mechanotransduction, respectively. This switch is triggered by the interaction between the SH3 domain of UNC-89 (titin/obscurin) and MEC-2. We suggest that this rigidity phase transition has a physiological role in frequency-dependent force transmission in mechanosensitive neurons during body wall touch. Our data demonstrate a function for the liquid and solid phases of MEC-2/stomatin condensates in facilitating transport or mechanotransduction, and a previously unidentified role for titin homologues in neurons.

Measuring age-dependent viscoelastic properties of organelles, cells and organisms via Time-Shared Optical Tweezer Microrheology

“…Liquid-liquid phase separation is relevant for the organization of many proteins within the cytoplasm of living cells[37, 38]. The correct localization and material properties of these biomolecular condensates is essential for proper cellular functions[6] and is thus under tight cellular control [39] and the uncontrolled transition of liquid-like condensates into insoluble and stiffened condensates often correlate with disease propagation where a higher degree of stiffening correlates with disease prognosis.…”

“…The complex shear modulus and surface tension of the material is then extracted from the active force measurement and passive bead displacement, with the assumption that the microsphere radius is considerably smaller than the protein droplet and that the viscosity of the dilute phase is known [41]. To relax these assumptions and simplify the experiment with a single trap, we performed TimSOM on MEC-2 condensates as a model for an age-dependent maturation process and compared these results to the dual trap assay[6] (Fig. 3).…”

“…How complex fluids deform and flow in relation to their chemical composition is the science of rheology[1]. The rheology of biological fluids is crucial for a variety of physiological and pathological processes[2, 3], including cell division[4], cell migration[5], mechanotransduction[6, 7, 8] and intracellular transport [9]. Recent data data indicates that alterations in the way cells and their components react to mechanical forces are linked to various diseases, such as cancer and neurodegeneration[3, 10, 11, 12].…”

“…Recent data data indicates that alterations in the way cells and their components react to mechanical forces are linked to various diseases, such as cancer and neurodegeneration[3, 10, 11, 12]. In particular, many phase-separated, liquid-like condensates exhibit age-dependent mechanical properties[13, 14, 6]. Their transition from a liquid-like to a gel/glassy state has been associated with a poor prognosis of many neurodegenerative disorders[13].…”

“…Optical tweezer-based active microrheology is a powerful technique for probing the mechanical properties of complex fluids in biological systems, such as the cytoplasm of living cells [4, 15], in living animals [16, 17] and biomolecular condensates [14, 6, 18]. This method involves the measurement of the motion of small particles suspended within a fluid (or embedded in a viscoelastic gel), due to an oscillating trapping potential [19].…”