Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 557, Issue -, Pages 323-328Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.03.156
Keywords
Shh; Gli signaling; RNF220; HDAC6; Aggresome; Autophagy
Categories
Funding
- National Natural Science Foundation of China [31671521, 31871483, 82060292]
- open project of State Key Laboratory of GeneticResources and Evolution [GREKF20-07]
- Youth Innovation Promotion Association of Chinese Academy of Sciences
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The study revealed that RNF220 fine tunes Shh signaling by regulating Glis polyubiquitination and nuclear translocation, while also affecting Shh signaling through EED in cerebellar development. In the cytoplasm, RNF220-induced Gli accumulation in the cytoskeletal fraction and degradation via autophagy.
Sonic hedgehog acts as a key mitogen to drive cell proliferation and as a morphogen to direct cell differentiation during embryonic development and adult tissue maintenance by controlling the activities of its transcriptional effectors Glis. We previously reported that RNF220 controls the nuclear translocation and subcellular localization of Glis by promoting their K63-linked polyubiquitination, through which it fine tunes Shh/Gli gradients during ventral spinal cord patterning. RNF220 also epigenetically regulates Shh signaling by targeting epifactor EED in cerebellar development. Here, we continued to study the molecular events underlying RNF220-mediated Shh regulation in the cytoplasm. The results showed that HDAC6 is required for RNF220-induced Gli accumulation in the cytoskeletal fraction and inclusion in aggresomes. In the cytoplasm, Glis polyubiquitinated by RNF220 are prone to interact with p62 and destined for autophagy-mediated degradation. Additionally, we showed that RNF220 inhibits the processing of Gli2 and Gli3 both in vitro and in vivo. Collectively, our studies shed new light on Shh signaling regulation. ? 2021 Elsevier Inc. All rights reserved.
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