Strength Through Unity: The Power of the Mega-Scaffold MACF1

The tight coordination of diverse cytoskeleton elements is required to support several dynamic cellular processes involved in development and tissue homeostasis. The spectraplakin-family of proteins are composed of multiple domains that provide versatility to connect different components of the cytoskeleton, including the actin microfilaments, microtubules and intermediates filaments. Spectraplakins act as orchestrators of precise cytoskeletal dynamic events. In this review, we focus on the prototypical spectraplakin MACF1, a protein scaffold of more than 700 kDa that coordinates the crosstalk between actin microfilaments and microtubules to support cell-cell connections, cell polarity, vesicular transport, proliferation, and cell migration. We will review over two decades of research aimed at understanding the molecular, physiological and pathological roles of MACF1, with a focus on its roles in developmental and cancer. A deeper understanding of MACF1 is currently limited by technical challenges associated to the study of such a large protein and we discuss ideas to advance the field.

Rhododenol Activates Melanocytes and Induces Morphological Alteration at Sub-Cytotoxic Levels

Rhododenol (RD), a whitening cosmetic ingredient, was withdrawn from the market due to RD-induced leukoderma (RIL). While many attempts have been made to clarify the mechanism underlying RIL, RIL has not been fully understood yet. Indeed, affected subjects showed uneven skin pigmentation, but the features are different from vitiligo, a skin hypopigmentary disorder, alluding to events more complex than simple melanocyte cytotoxicity. Here, we discovered that rhododenol treatment reduced the number of melanocytes in a pigmented 3D human skin model, Melanoderm™, confirming the melanocyte toxicity of RD. Of note, melanocytes that survived in the RD treated tissues exhibited altered morphology, such as extended dendrites and increased cell sizes. Consistently with this, sub-cytotoxic level of RD increased cell size and elongated dendrites in B16 melanoma cells. Morphological changes of B16 cells were further confirmed in the immunocytochemistry of treated cells for actin and tubulin. Even more provoking, RD up-regulated the expression of tyrosinase and TRP1 in the survived B16 cells. Evaluation of mRNA expression of cytoskeletal proteins suggests that RD altered the cytoskeletal dynamic favoring cell size expansion and melanosome maturation. Collectively, these results suggest that RD not only induces cytotoxicity in melanocytes but also can lead to a profound perturbation of melanocyte integrity even at sub-cytotoxic levels.