Dataset Information

Interaction of tau with HNRNPA2B1 and N⁶-methyladenosine RNA mediates the progression of tauopathy.

ABSTRACT: The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N⁶-methyladenosine (m⁶A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m⁶A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m⁶A and the m⁶A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m⁶A that contributes to the integrated stress response of oTau.

SUBMITTER: Jiang L

PROVIDER: S-EPMC8541906 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Interaction of tau with HNRNPA2B1 and N<sup>6</sup>-methyladenosine RNA mediates the progression of tauopathy.

Jiang Lulu L Lin Weiwei W Zhang Cheng C Ash Peter E A PEA Verma Mamta M Kwan Julian J van Vliet Emily E Yang Zhuo Z Cruz Anna Lourdes AL Boudeau Samantha S Maziuk Brandon F BF Lei Shuwen S Song Jaehyup J Alvarez Victor E VE Hovde Stacy S Abisambra Jose F JF Kuo Min-Hao MH Kanaan Nicholas N Murray Melissa E ME Crary John F JF Zhao Jian J Cheng Ji-Xin JX Petrucelli Leonard L Li Hu H Emili Andrew A Wolozin Benjamin B

Molecular cell 20210827 20

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal ...[more]

PMID: 34453888

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Project description:BackgroundEpithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown.MethodsThe correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining.ResultsThe expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance.ConclusionsMIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

Dataset Information

Interaction of tau with HNRNPA2B1 and N⁶-methyladenosine RNA mediates the progression of tauopathy.

Publications

Interaction of tau with HNRNPA2B1 and N<sup>6</sup>-methyladenosine RNA mediates the progression of tauopathy.

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Dataset Information

Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy.

Publications

Interaction of tau with HNRNPA2B1 and N<sup>6</sup>-methyladenosine RNA mediates the progression of tauopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Interaction of tau with HNRNPA2B1 and N⁶-methyladenosine RNA mediates the progression of tauopathy.