bims-ershed 2022-08-21 papers

Nucleic Acids Res. 2022 Aug 18. pii: gkac690. [Epub ahead of print]

Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.

Nguyen Thi Kim Oanh, Ho-Soo Lee, Yong-Hyun Kim, Sunwoo Min, Yeon-Ji Park, June Heo, Yong-Yea Park, Won-Chung Lim, Hyeseong Cho.

Cells are constantly challenged by genotoxic stresses that can lead to genome instability. The integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals.

DOI: https://doi.org/10.1093/nar/gkac690

Mol Carcinog. 2022 Aug 17.

TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.

Saie Mogre, Nicholas Blazanin, Hailey Walsh, Jack Ibinson, Chase Minnich, Chih-Chi Andrew Hu, Adam B Glick.

Transforming Growth Factor β1 (TGFβ1) is a critical regulator of tumor progression in response to HRas. Recently, TGFβ1 has been shown to trigger ER stress in many disease models; however, its role in oncogene-induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol-requiring enzyme 1α (IRE1α) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1α and (PKR)-like endoplasmic reticulum kinase (PERK) to mediate the tumor-suppressive roles of TGFβ1 in mouse keratinocytes expressing mutant forms of HRas. TGFβ1 suppressed IRE1α phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously activating the PERK pathway. However, the increase in ER stress indicated an uncoupling of ER stress and IRE1α activation by TGFβ1. Pharmacological and genetic approaches demonstrated that TGFβ1-dependent dephosphorylation of IRE1α was mediated by PERK through RNA Polymerase II Associated Protein 2 (RPAP2), a PERK-dependent IRE1α phosphatase. In addition, TGFβ1-mediated growth arrest in oncogenic HRas keratinocytes was partially dependent on PERK-induced IRE1α dephosphorylation and inactivation. Together, these results demonstrate a critical cross-talk between UPR proteins that is important for TGFβ1-mediated tumor suppressive responses.

Keywords: ER stress; HRas; IRE1α; PERK; TGFβ1; proliferation; unfolded protein response

DOI: https://doi.org/10.1002/mc.23453

Theriogenology. 2022 Aug 03. pii: S0093-691X(22)00279-5. [Epub ahead of print]191 132-140

Spliced X-box binding protein 1 (XBP1s) protects spermatogonial stem cells (SSCs) from lipopolysaccharide (LPS)-induced damage by regulating the testicular microenvironment.

Wenjing Xu, Yumei Yang, Yunxiang Li, Donghui Yang, Shicheng Wan, Na Li, Jinlian Hua.

XBP1 is a transcription factor that plays a central role in controlling cellular responses to endoplasmic reticulum stress (ERS). Under stress conditions, the transcriptionally active form of XBP1 is generated by splicing of XBP1 mRNA by the ER-resident protein inositol-requiring enzyme-1α (IRE1α). This study aimed to investigate the role of XBP1 in male reproductive disorders. XBP1s-overexpressing goat spermatogonial stem cells (gSSCs) showed higher proliferative ability in vitro and in vivo. These cells also showed higher antioxidant capacity. In comparison, XBP1 knockdown significantly suppressed proliferation. Further analysis showed that XBP1 could stimulate the secretion of IL-6 from macrophages. Overall, the results indicate that XBP1s functions to enhance the proliferation ability and antioxidant capacity of gSSCs, potentially through a mechanism involving the regulation of gSSCs by macrophages.

Keywords: Goat; Proliferation; SSCs; XBP1s

DOI: https://doi.org/10.1016/j.theriogenology.2022.07.014