bims-ershed 2022-07-31 papers

Cell Death Dis. 2022 Jul 28. 13(7): 655

XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP.

Kyung-Woo Lee, Hui-Ra Hong, Ji-Sun Lim, Kyung-Phil Ko, Min-Goo Lee, Sung-Gil Chi.

X-linked inhibitor of apoptosis-associated factor-1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in many human cancers. Despite accumulating evidence for the pro-apoptotic role for XAF1 under various stressful conditions, its involvement in endoplasmic reticulum (ER) stress response remains undefined. Here, we report that XAF1 increases cell sensitivity to ER stress and acts as a molecular switch in unfolded protein response (UPR)-mediated cell-fate decisions favoring apoptosis over adaptive autophagy. Mechanistically, XAF1 interacts with and destabilizes ER stress sensor GRP78 through the assembly of zinc finger protein 313 (ZNF313)-mediated destruction complex. Moreover, XAF1 expression is activated through PERK-Nrf2 signaling and destabilizes C-terminus of Hsc70-interacting protein (CHIP) ubiquitin E3 ligase, thereby blocking CHIP-mediated K63-linked ubiquitination and subsequent phosphorylation of inositol-required enzyme-1α (IRE1α) that is involved in in the adaptive ER stress response. In tumor xenograft assays, XAF1-/- tumors display substantially lower regression compared to XAF1+/+ tumors in response to cytotoxic dose of ER stress inducer. XAF1 and GRP78 expression show an inverse correlation in human cancer cell lines and primary breast carcinomas. Collectively this study uncovers an important role for XAF1 as a linchpin to govern the sensitivity to ER stress and the outcomes of UPR signaling, illuminating the mechanistic consequence of XAF1 inactivation in tumorigenesis.

DOI: https://doi.org/10.1038/s41419-022-05112-0

Trends Biochem Sci. 2022 Jul 20. pii: S0968-0004(22)00168-2. [Epub ahead of print]

Oxidative protein folding fidelity and redoxtasis in the endoplasmic reticulum.

Lei Wang, Chih-Chen Wang.

In eukaryotic cells, oxidative protein folding occurs in the lumen of the endoplasmic reticulum (ER), catalyzed by ER sulfhydryl oxidase 1 (Ero1) and protein disulfide isomerase (PDI). The efficiency and fidelity of oxidative protein folding are vital for the function of secretory cells. Here, we summarize oxidative protein folding in yeast, plants, and mammals, and discuss how the conformation and activity of human Ero1-PDI machinery is regulated through various post-translational modifications (PTMs). We propose that oxidative protein folding fidelity and ER redox homeostasis are maintained by both the precise control of Ero1 oxidase activity and the division of labor between PDI family members. We also discuss how deregulated Ero1-PDI functions contribute to human diseases and can be leveraged for therapeutic interventions.

Keywords: ER sulfhydryl oxidase 1 (Ero1); disulfide bond; endoplasmic reticulum (ER); oxidative protein folding; protein disulfide isomerase (PDI); redox homeostasis

DOI: https://doi.org/10.1016/j.tibs.2022.06.011

J Cell Sci. 2022 Jul 27. pii: jcs.259993. [Epub ahead of print]

Proteomic analysis of the actin cortex in interphase and mitosis.

Neza Vadnjal, Sami Nourreddine, Geneviève Lavoie, Murielle Serres, Philippe P Roux, Ewa K Paluch.

Many animal cell shape changes are driven by gradients in the contractile tension of the actomyosin cortex, a thin cytoskeletal network supporting the plasma membrane. Elucidating cortical tension control is thus essential for understanding cell morphogenesis. Increasing evidence shows that alongside myosin activity, actin network organisation and composition are key to cortex tension regulation. However, due to poor understanding of how cortex composition changes when tension changes, which cortical components are important remains unclear. In this Resource article, we compared cortices from cells with low and high cortex tensions. We purified cortex-enriched fractions from cells in interphase and mitosis, as mitosis is characterised by high cortical tension. Mass spectrometry analysis identified 922 proteins consistently represented in both interphase and mitotic cortices. Focusing on actin-related proteins narrowed down the list to 238 candidate regulators of the mitotic cortical tension increase. Among these candidates, we found a role for septins in mitotic cell rounding control. Overall, our study provides a comprehensive dataset of candidate cortex regulators, paving the way for systematic investigations of the regulation of cell surface mechanics.

Keywords: Actin; Cell cortex; Cell division; Cortical tension; Mass specotometry; Septin

DOI: https://doi.org/10.1242/jcs.259993