kinesin recruitment by adapter SKIP on melanosomes is dynamically controlled by LC3B phosphorylation

Anterograde melanosome transport is essential for adaptive skin tanning response. However, the molecular components involved, their interplay and regulation by external cues in melanosome transport remain under-explored. Silencing of kinesin motors revealed that several members including the established KIF5B and a novel candidate KIF1B, mediate melanosome movement. The camouflage behaviour of zebrafish embryos induced by incident light or α -MSH requires kif1b, suggesting a conserved melanosome transport machinery across vertebrates. Interestingly, the peri-nuclear melanosome accumulation upon kinesin knockdown is recapitulated by the silencing of autophagy effector MAP1LC3B (LC3B). Pull-down assays identified KIF1B, but not KIF5B, to be the LC3B-associated kinesin. LC3B binds the adapter SKIP via its LIR docking region that is proximal to Thr12 residue, a site for phosphorylation by Protein Kinase A. We demonstrate that phosphorylation of LC3B at Thr12 is stimulated by α-MSH, which potentiates the anterograde melanosome transport. Thereby, our study, identifies a novel kinesin motor KIF1B for melanosome movement and establishes LC3B as the key molecular component that facilitates α-MSH responsive mobilization of melanosomes.Key HighlightsKinesin screen reveals non-redundant use of KIF5B, KIF1B motors for melanosome transportkif1b is required for camouflage response in zebrafish and melanosome movement in mammalsN-terminal region of LC3B interacts with adapter SKIP and couples kinesin KIF1Bα-MSH activates PKA-mediated phosphorylation of LC3B to potentiate anterograde movementSignificanceMelanosomes are lysosome related organelles containing melanin pigment, that are synthesized in melanocytes and transferred to the recipient keratinocytes of skin. This involves long range melanosome movement within melanocytes to reach cell periphery for the transfer to follow. Physiologically, UV protection involves local secretion of melanocyte stimulating hormone (α-MSH) that acts on melanocytes to promote skin tanning response. Herein, we investigate the components involved in this process and establish that the melanosome movement is dynamically controlled by α-MSH through phosphorylation of LC3B. These findings establish the mechanism behind the rapid distribution of melanosomes during tanning response and provide opportunity to intervene for sun protection.

Beyond pigmentation: signs of liver protection during afamelanotide treatment in Swiss patients with erythropoietic protoporphyria, an observational study

Erythropoietic protoporphyria (EPP) is an ultra-rare inherited disorder with overproduction of protoporphyrin in maturating erythroblasts. This excess protoporphyrin leads to incapacitating phototoxic burns in sunlight exposed skin. Its biliary elimination causes cholestatic liver injury in 20% and terminal liver failure in 4% of EPP patients. Thereby, the risk of liver injury increases with increasing erythrocyte protoporphyrin concentrations. Afamelanotide, an α-melanocyte-stimulating hormone (MSH) analog inducing skin pigmentation, was shown to improve sunlight tolerance in EPP. Beyond this well-known effect on pigmentation, the MSHs have liver-protective effects and improve survival of maturating erythroblasts, effects described in animal or in vitro models to date only. We investigated whether afamelanotide treatment in EPP has effects on erythropoiesis, protoporphyrin concentrations, and liver injury by analyzing retrospectively our long-term safety data. Methods: From the 47 Swiss EPP-patients treated at our center since 2006, we included those 38 patients in the current analysis who received at least one afamelanotide dose between 2016 and 2018 and underwent regular laboratory testing before and during the treatment. We compared the means of pretreatment measurements with those during the treatment. Results: Protoporphyrin concentrations dropped from 21.39 ± 11.12 (mean ± SD) before afamelanotide to 16.83 ± 8.24 µmol/L ( p < .0001) during treatment. Aspartate aminotransferase decreased from 26.67 ± 13.16 to 22.9 ± 7.76 IU/L ( p = .0146). For both entities, patients with higher values showed a more progressive decrease, indicating a risk reduction of EPP-related liver disease. The pre-existing hypochromia and broad mean red-cell distribution width were further augmented under afamelanotide. This was more likely due to an influence of afamelanotide on maturating erythroblasts than due to an exacerbated iron deficiency, as mean zinc-protoporphyrin decreased significantly and ferritin remained unchanged. No serious afamelanotide-related adverse events were observed for a total of 240 treatment years. Conclusion: Our findings point to a protective effect of afamelanotide on erythroblast maturation and protoporphyrin-induced liver injury. Plain Language summary Afamelanotide, a skin tanning hormone, may protect patients with erythropoietic protoporphyria not only from skin burns, but also from liver injury associated with the disease. Patients with erythropoietic protoporphyria (EPP), an inherited metabolic disease, suffer from light-induced skin burns and liver injury elicited by the accumulated light sensitizer protoporphyrin. The excess protoporphyrin is produced in red cell precursors in the bone marrow, and it is eliminated from the body via the liver and bile. A high protoporphyrin excretion burden damages the liver cells, the risk for this increases with higher protoporphyrin concentrations. About 20% of EPP patients show some sign of liver injury and 4% develop life-threatening liver dysfunction. Afamelanotide, closely related to natural α-melanocyte stimulating hormone (MSH), induces skin tanning. This effect protects EPP patients from light-induced skin burns as shown in previous studies. We have treated Swiss EPP patients with afamelanotide since 2006, and we regularly perform safety tests of this treatment. Recent in vitro and animal studies demonstrated α-MSH effects other than skin tanning, including an improved synthesis of red blood cell precursors in the bone-marrow and protection of the liver from experimentally induced damage. Until now, it is unknown whether afamelanotide has similar effects in the human organism. To study this question, we analyzed retrospectively the safety laboratory data of 38 Swiss patients, who received at least one dose of afamelanotide from 2016 to 2019. We found that both, the average protoporphyrin concentrations and aspartate aminotransferase, a test for liver function, improved during afamelanotide treatment as compared to before. We concluded that afamelanotide applied to EPP patients to protect them from light-induced skin burns also may reduce their risk of liver injury.

Cosmopolitan Whiteness

Previous scholarship on the immense popularity of skin-whitening frames this practice as revealing women’s desire to emulate whiteness and upper class White populations. Others have focused on whitening practices to highlight the working of racialized color hierarchy and European/Euro-American hegemony in local and global contexts. This article breaks away from these established theoretical trajectories by arguing that desire for “whiteness” is not the same as desire for “Caucasian whiteness.” Examining advertisements for skin-whitening products in the Indonesian version of Cosmopolitan and skin-tanning products in the American version of Cosmopolitan, the author points out the construction of “cosmopolitan whiteness.” Whiteness is not simply racialized or nationalized as such, but transnationalized. Whiteness is represented as “cosmopolitanness,” embodying transnational mobility.

CO RELATIVE STUDY OF BHRAJAK PITTA AND MELANIN

Dosa dhatu mala are the basic principles of Ayurveda. In Ayurveda vata,pitta, kapha are the main 3 types of dosa. According to Vagbhata pitta has these main function namely pakti (digestion),ushma(maintain proper body temperature),darshan (vision), kshudha(hunger), trushna(thirst), prabha (lustre) to skin ,medha( intellect). Pathological increase in Pitta causes yellow coloured skin and eyes and decrease in Pitta causes loss of lustre and low glorification (prabhahani). pitta has five subtypes Aalochak ,Ranjak ,Sadhak ,Pachak and Bhrajak pitta . Bhrajak pitta is located in skin and its functions are regulation of body heat and maintain normal skin colour and absorption and digestion of medicine applied on skin. According to modern science the colour of skin depends upon melanin concentration. Excess level of melanin results in skin tanning while absence of melanin causes albinism. Co- relative study of Bhrajak Pitta and melanin may helpful to ayurvedic students to understand ayurvedic concept Bhrajak pitta in modern point of view hence, detail study of Bhrajak pitta and Melanin in has been elaborated in this article.