Antiapoptotic Protein FAIM2 is targeted by miR-3202, and DUX4 via TRIM21, leading to cell death and defective myogenesis

Hossam A.N. Soliman, Erik A Toso, Inas E. Darwish, Samia M. Ali, Michael Kyba

Research output: Contribution to journalArticlepeer-review

Abstract

Inappropriate expression of DUX4, a transcription factor that induces cell death at high levels of expression and impairs myoblast differentiation at low levels of expression, leads to the development of facioscapulohumeral muscular dystrophy (FSHD), however, the pathological mechanisms downstream of DUX4 responsible for muscle loss are poorly defined. We performed a screen of 1972 miR inhibitors for their ability to interfere with DUX4-induced cell death of human immortalized myoblasts. The most potent hit identified by the screen, miR-3202, is known to target the antiapoptotic protein FAIM2. Inhibition of miR-3202 led to the upregulation of FAIM2, and remarkably, expression of DUX4 led to reduced cellular levels of FAIM2. We show that the E3 ubiquitin ligase and DUX4 target gene, TRIM21, is responsible for FAIM2 degradation downstream of DUX4. Human myoblasts overexpressing FAIM2 showed increased resistance to DUX4-induced cell death, whereas in wild-type cells FAIM2 knockdown resulted in increased apoptosis and failure to differentiate into myotubes. The necessity of FAIM2 for myogenic differentiation of WT cells led us to test the effect of FAIM2 overexpression on the impairment of myogenesis by DUX4. Strikingly, FAIM2 overexpression rescued the myogenic differentiation defect caused by low-level expression of DUX4. These data implicate FAIM2 levels, modulated by DUX4 through TRIM21, as an important factor mediating the pathogenicity of DUX4, both in terms of cell viability and myogenic differentiation, and thereby open a new avenue of investigation towards drug targets in FSHD.

Original languageEnglish (US)
Article number405
JournalCell Death and Disease
Volume13
Issue number4
DOIs
StatePublished - Apr 2022

Bibliographical note

Funding Information:
This work was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR055685) and the Egyptian Cultural and Education Bureau Joint Supervision Program (JS 3740). We thank the University of Minnesota Stem Cell Institute for provision of the miR inhibitor library. We thank Cynthia Faraday for graphical design.

Funding Information:
This work was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR055685) and the Egyptian Cultural and Education Bureau Joint Supervision Program (JS 3740). We thank the University of Minnesota Stem Cell Institute for provision of the miR inhibitor library. We thank Cynthia Faraday for graphical design.

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Antiapoptotic Protein FAIM2 is targeted by miR-3202, and DUX4 via TRIM21, leading to cell death and defective myogenesis'. Together they form a unique fingerprint.

Cite this