UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation

Manivannan Subramanian, Seung Jae Hyeon, Tanuza Das, Yoon Seok Suh, Yun Kyung Kim, Jeong Soo Lee, Eun Joo Song, Hoon Ryu, Kweon Yu

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


The formation of hyperphosphorylated intracellular Tau tangles in the brain is a hallmark of Alzheimer’s disease (AD). Tau hyperphosphorylation destabilizes microtubules, promoting neurodegeneration in AD patients. To identify suppressors of tau-mediated AD, we perform a screen using a microRNA (miR) library in Drosophila and identify the miR-9 family as suppressors of human tau overexpression phenotypes. CG11070, a miR-9a target gene, and its mammalian orthologue UBE4B, an E3/E4 ubiquitin ligase, alleviate eye neurodegeneration, synaptic bouton defects, and crawling phenotypes in Drosophila human tau overexpression models. Total and phosphorylated Tau levels also decrease upon CG11070 or UBE4B overexpression. In mammalian neuroblastoma cells, overexpression of UBE4B and STUB1, which encodes the E3 ligase CHIP, increases the ubiquitination and degradation of Tau. In the Tau-BiFC mouse model, UBE4B and STUB1 overexpression also increase oligomeric Tau degradation. Inhibitor assays of the autophagy and proteasome systems reveal that the autophagy-lysosome system is the major pathway for Tau degradation in this context. These results demonstrate that UBE4B, a miR-9 target gene, promotes autophagy-mediated Tau degradation together with STUB1, and is thus an innovative therapeutic approach for AD.

Original languageEnglish
Article number3291
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2021

Bibliographical note

Funding Information:
Drosophila stocks were obtained from Bloomington Sock Center (Bloomington, IN, USA) and Vienna Drosophila RNAi Center (VDRC, Vienna, Austria). This work was supported by grants from KRIBB Research Initiative Program, National Research Council of Science & Technology (CRC-15-04-KIST), KIST (2E30951, 2E30954 and 2E30962), and National Research Foundation of Korea (2015R1A5A1009024, 2017HID3A1A02054608, 2018M3C7A1056894, 2019R1A2C 2004052, 2019R1A2C2004149, 2020R1A4A4079494, and 2020M3E5D9079742).

Publisher Copyright:
© 2021, The Author(s).


Dive into the research topics of 'UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation'. Together they form a unique fingerprint.

Cite this