TRIM28 functions as a negative regulator of aggresome formation

Jeeyoon Chang, Hyun Jung Hwang, Byungju Kim, Yeon Gil Choi, Joori Park, Yeonkyoung Park, Ban Seok Lee, Heedo Park, Min Ji Yoon, Jae Sung Woo, Chungho Kim, Man Seong Park, Jong Bong Lee, Yoon Ki Kim

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Selective recognition and elimination of misfolded polypeptides are crucial for protein homeostasis. When the ubiquitin-proteasome system is impaired, misfolded polypeptides tend to form small cytosolic aggregates and are transported to the aggresome and eventually eliminated by the autophagy pathway. Despite the importance of this process, the regulation of aggresome formation remains poorly understood. Here, we identify TRIM28/TIF1β/KAP1 (tripartite motif containing 28) as a negative regulator of aggresome formation. Direct interaction between TRIM28 and CTIF (cap binding complex dependent translation initiation factor) leads to inefficient aggresomal targeting of misfolded polypeptides. We also find that either treatment of cells with poly I:C or infection of the cells by influenza A viruses triggers the phosphorylation of TRIM28 at S473 in a way that depends on double-stranded RNA-activated protein kinase. The phosphorylation promotes association of TRIM28 with CTIF, inhibits aggresome formation, and consequently suppresses viral proliferation. Collectively, our data provide compelling evidence that TRIM28 is a negative regulator of aggresome formation. Abbreviations: BAG3: BCL2-associated athanogene 3; CTIF: CBC-dependent translation initiation factor; CED: CTIF-EEF1A1-DCTN1; DCTN1: dynactin subunit 1; EEF1A1: eukaryotic translation elongation factor 1 alpha 1; EIF2AK2: eukaryotic translation initiation factor 2 alpha kinase 2; HDAC6: histone deacetylase 6; IAV: influenza A virus; IP: immunoprecipitation; PLA: proximity ligation assay; polypeptidyl-puro: polypeptidyl-puromycin; qRT-PCR: quantitative reverse-transcription PCR; siRNA: small interfering RNA.

Original languageEnglish
Pages (from-to)4231-4248
Number of pages18
JournalAutophagy
Volume17
Issue number12
DOIs
Publication statusPublished - 2021

Bibliographical note

Funding Information:
This work was supported by a NRF (National Research Foundation) of Korea grant funded by the Korean government (Ministry of Science, ICT and Future Planning; NRF-2015R1A3A2033665 and 2018R1A5A1024261) and by a Korea University Future Research grant. We thank Dr. Byung-Yoon Ahn for providing the MEFs

Publisher Copyright:
© 2021 Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • Aggrephagy
  • CTIF
  • DCTN1
  • EEF1A1
  • EIF2AK2
  • influenza A virus

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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