bims-ershed 2023-04-16 papers

Issue of 2023‒04‒16
three papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

J Cell Biol. 2023 May 01. pii: e202304013. [Epub ahead of print]222(5):

Disagreement among the three musketeers of the unfolded protein response.

Jipa and Juhász preview results from the lab of Tao Wang (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202208147) which show a surprising antagonism between two branches of the unfolded protein response that dictates disease progression in a model of autosomal dominant retinitis pigmentosa.

DOI: https://doi.org/10.1083/jcb.202304013

Open Biol. 2023 Apr;13(4): 230008

The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response.

Rima Naït-Saïdi, Aymeric Chartier, Emmanuelle Abgueguen, Philippe Guédat, Martine Simonelig.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease characterized by the progressive degeneration of specific muscles. OPMD is due to a mutation in the gene encoding poly(A) binding protein nuclear 1 (PABPN1) leading to a stretch of 11 to 18 alanines at N-terminus of the protein, instead of 10 alanines in the normal protein. This alanine tract extension induces the misfolding and aggregation of PABPN1 in muscle nuclei. Here, using Drosophila OPMD models, we show that the unfolded protein response (UPR) is activated in OPMD upon endoplasmic reticulum stress. Mutations in components of the PERK branch of the UPR reduce muscle degeneration and PABPN1 aggregation characteristic of the disease. We show that oral treatment of OPMD flies with Icerguastat (previously IFB-088), a Guanabenz acetate derivative that shows lower side effects, also decreases muscle degeneration and PABPN1 aggregation. Furthermore, the positive effect of Icerguastat depends on GADD34, a key component of the phosphatase complex in the PERK branch of the UPR. This study reveals a major contribution of the ER stress in OPMD pathogenesis and provides a proof-of-concept for Icerguastat interest in future pharmacological treatments of OPMD.

Keywords: Drosophila model; GADD34; Icerguastat/IFB-088; OPMD; PEK/PERK; unfolded protein response

DOI: https://doi.org/10.1098/rsob.230008

Cell Rep. 2023 Apr 13. pii: S2211-1247(23)00412-6. [Epub ahead of print]42(4): 112401

Cell-to-cell variability in Myc dynamics drives transcriptional heterogeneity in cancer cells.

Chad Liu, Takamasa Kudo, Xin Ye, Karen Gascoigne.

Cell-to-cell heterogeneity is vital for tumor evolution and survival. How cancer cells achieve and exploit this heterogeneity remains an active area of research. Here, we identify c-Myc as a highly heterogeneously expressed transcription factor and an orchestrator of transcriptional and phenotypic diversity in cancer cells. By monitoring endogenous c-Myc protein in individual living cells, we report the surprising pulsatile nature of c-Myc expression and the extensive cell-to-cell variability in its dynamics. We further show that heterogeneity in c-Myc dynamics leads to variable target gene transcription and that timing of c-Myc expression predicts cell-cycle progression rates and drug sensitivities. Together, our data advocate for a model in which cancer cells increase the heterogeneity of functionally diverse transcription factors such as c-Myc to rapidly survey transcriptional landscapes and survive stress.

Keywords: CP: Cancer; CP: Cell biology; Myc; cancer; cell-to-cell heterogeneity; gene expression; transcription

DOI: https://doi.org/10.1016/j.celrep.2023.112401