TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans

Abstract

Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6 −/− ) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6 −/− old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.

IBF-R Regulates IRE1α Post-Translational Modifications and ER Stress in High-Fat Diet-Induced Obese Mice

“…In obesity showing ER stress conditions, we asserted that obesity-induced and phosphorylation-independent modifications in IRE1α might suppress ribonuclease activity selectively. We observed a substantial rise in iNOS expression in HFD conditions, which coincides with the decrease in the sXBP1 activity “the nuclear translocation of sXBP-1” in adipose tissue of obese mice ( Figure 3 f) [ 16 ]. This coincidence represents an obesity model featuring chronic metabolic inflammation [ 21 , 22 , 23 ], whereas IBF-R significantly suppressed the iNOS level.…”

“…IBF-R demonstrated its potentials in regulating adipogenesis by sustaining redox-linked PTMs and ER homeostasis. Moreover, previously, we have demonstrated that severe redox-mediated PTMs of IRE1α impairs ER function and sustain ER stress in aging/metabolic disorder models suggesting the S-nitrosylation of IRE1α affects its endoribonuclease activity, thereby impairs sXBP1, leading to inflammation [ 16 ]. In addition, the increased iNOS-induced metaflammation is associated with impaired XBP1 processing in obesity [ 31 ].…”

“…HMWC’s were detected by following previous reports [ 16 ]. Homogenized whole adipose tissues were used to detect HMWC of Protein Disulfide Isomerase (PDI, ADI-SPA-891-F, Enzo Life Sciences, Inc., Farmingdale, NY, USA).…”

Methyltransferase-like 3 aggravates endoplasmic reticulum stress in preeclampsia by targeting TMBIM6 in YTHDF2-dependent manner

“…Previous studies have shown that TMBIM6 is essential for ER homeostasis (Lebeaupin et al 2020 ; Bhattarai et al 2021 ). The m 6 A sites of TMBIM6 were predicted using two databases, RMBase v2.0 ( http://rna.sysu.edu.cn/rmbase/ ) and M6A2Target ( http://m6a2target.canceromics.org/ ) (Deng et al 2021 ; Xuan et al 2018 ).…”

“…The transmembrane Bax inhibitor motif containing 6 (TMBIM6), also known as Bax interactivator-1 (BI-1), is a highly conserved transmembrane protein primarily located in the ER (Lebeaupin et al 2020 ). TMBIM6 inhibits Bax-induced apoptosis, shows beneficial effects against ER stress and calcium imbalance, and possesses anti-inflammatory and anti-oxidative properties (Lebeaupin et al 2020 ; Han et al 2021 ; Bhattarai et al 2021 ). TMBIM6 can inhibit ER stress-induced apoptosis via multiple mechanisms, such as by regulating the calcium flux in the ER lumen, activating the PERK/ATF4/CHOP pathway, and limiting reactive oxygen species (ROS) production (Lebeaupin et al 2020 ).…”