Summary
In selective autophagy, receptors are central for cargo selection and delivery. However, it remains yet unclear whether and how multiple autophagy receptors might form complex and function concertedly to control autophagy. Optineurin (OPTN), implicated genetically in glaucoma and amyotrophic lateral sclerosis, was a recently identified autophagy receptor. Here we report that tumor suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62/SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux. Interestingly, the K48-linked polyubiquitin chains that HACE1 conjugates onto OPTN might predominantly target OPTN for autophagic degradation. By demonstrating that the HACE1-OPTN axis synergistically suppresses growth and tumorigenicity of lung cancer cells, our findings may open an avenue for developing autophagy-targeted therapeutic intervention into cancer.
Summary
Endothelium in embryonic hematopoietic tissues generates hematopoietic
stem/progenitor cells; however, it is unknown how its unique potential is
specified. We show that transcription factor Scl/Tal1 is essential for both
establishing the hematopoietic transcriptional program in hemogenic endothelium
and preventing its misspecification to a cardiomyogenic fate.
Scl−/− embryos activated a cardiac
transcriptional program in yolk sac endothelium, leading to the emergence of
CD31+Pdgfrα+ cardiogenic precursors that
generated spontaneously beating cardiomyocytes. Ectopic cardiogenesis was also
observed in Scl−/− hearts, where the
disorganized endocardium precociously differentiated into cardiomyocytes.
Induction of mosaic deletion of Scl in
Sclfl/fl Rosa26Cre-ERT2 embryos
revealed a cell-intrinsic, temporal requirement for Scl to prevent
cardiomyogenesis from endothelium.
Scl−/− endothelium also
upregulated the expression of Wnt antagonists, which promoted rapid
cardiomyocyte differentiation of ectopic cardiogenic cells. These results reveal
unexpected plasticity in embryonic endothelium such that loss of a single master
regulator can induce ectopic cardiomyogenesis from endothelial cells.
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