Identification of FIP200 interaction with the TSC1–TSC2 complex and its role in regulation of cell size control

FIP200 (focal adhesion kinase [FAK] family interacting protein of 200 kD) is a newly identified protein that binds to the kinase domain of FAK and inhibits its kinase activity and associated cellular functions. Here, we identify an interaction between FIP200 and the TSC1–TSC2 complex through FIP200 binding to TSC1. We found that association of FIP200 with the TSC1–TSC2 complex correlated with its ability to increase cell size and up-regulate S6 kinase phosphorylation but was not involved in the regulation of cell cycle progression. Conversely, knockdown of endogenous FIP200 by RNA interference reduced S6 kinase phosphorylation and cell size, which required TSC1 but was independent of FAK. Furthermore, overexpression of FIP200 reduced TSC1–TSC2 complex formation, although knockdown of endogenous FIP200 by RNA interference did not affect TSC1–TSC2 complex formation. Lastly, we showed that FIP200 is important in nutrient stimulation-induced, but not energy- or serum-induced, S6 kinase activation. Together, these results suggest a cellular function of FIP200 in the regulation of cell size by interaction with the TSC1–TSC2 complex

Role of FIP200 in cardiac and liver development and its regulation of TNFα and TSC–mTOR signaling pathways

Focal adhesion kinase family interacting protein of 200 kD (FIP200) has been shown to regulate diverse cellular functions such as cell size, proliferation, and migration in vitro. However, the function of FIP200 in vivo has not been investigated. We show that targeted deletion of FIP200 in the mouse led to embryonic death at mid/late gestation associated with heart failure and liver degeneration. We found that FIP200 knockout (KO) embryos show reduced S6 kinase activation and cell size as a result of increased tuberous sclerosis complex function. Furthermore, FIP200 KO embryos exhibited significant apoptosis in heart and liver. Consistent with this, FIP200 KO mouse embryo fibroblasts and liver cells showed increased apoptosis and reduced c-Jun N-terminal kinase phosphorylation in response to tumor necrosis factor (TNF) α stimulation, which might be mediated by FIP200 interaction with apoptosis signal–regulating kinase 1 (ASK1) and TNF receptor–associated factor 2 (TRAF2), regulation of TRAF2–ASK1 interaction, and ASK1 phosphorylation. Together, our results reveal that FIP200 functions as a regulatory node to couple two important signaling pathways to regulate cell growth and survival during mouse embryogenesis

Are the preoperative albumin levels and the albumin to fibrinogen ratio the risk factors for acute infection after primary total joint arthroplasty?

BackgroundAcute infection, such as periprosthetic joint infection and superficial surgical site infection, after primary total joint arthroplasty (TJA) is a serious complication, and its risk factors remain controversial. This study aimed to identify the risk factors for acute infection after primary TJA, especially the serological indicators that reflect preoperative nutritional statuses, such as albumin level and albumin to fibrinogen ratio (AFR).MethodsWe retrospectively reviewed patients who underwent elective primary hip or knee arthroplasty at our institution from 2009 to 2021. Potential risk factors of acute infection and demographic information were extracted from an electronic health record. Patients who suffered acute infection, such as PJI or SSI, after TJA were considered the study group. Non-infected patients were matched 1:2 with the study group according to sex, age, the involved joint (hip or knee), and year of surgery (control group). The variables of potential risk factors for acute postoperative infection (demographic characteristics, preoperative comorbidities and drug use, operative variables, and laboratory values) were collected and evaluated by regression analysis. Restrictive cubic spline regression analysis was also used to examine the relationship between preoperative serum albumin levels and acute postoperative infection.ResultsWe matched 162 non-infected patients with 81 patients who suffered from acute postoperative infection. Among the patients who suffered from acute infection within 90 days after TJA, 18 were diagnosed with periprosthetic joint infection and 63 with surgical site infection. Low albumin levels were strongly associated with acute postoperative infection (95% confidence interval, 0.822–0.980; P = 0.015). This risk increased as preoperative albumin levels decreased, with a negative dose-response relationship (Poverall = 0.002; Pnonlinear = 0.089). However, there was no significant association between the AFR and acute infection after primary TJA (P = 0.100).ConclusionThere is currently insufficient evidence to confirm the relationship between preoperative AFR and acute infection after elective primary TJA, while a lower preoperative albumin level is an independent risk factor for acute infection with a negative dose-response relationship. This suggests that optimal nutritional management may be benefited before elective primary TJA

BAP1 suppresses tumor development by inducing ferroptosis upon SLC7A11 repression

The tumor suppressor BRCA1-associated protein 1 (BAP1) is a deubiquitinase that removes histone 2A ubiquitination. How BAP1 suppresses tumor development remains elusive. Our recent study identified the cystine transporter solute carrier family 7 member 11 (SLC7A11) as a critical BAP1 target, and showed that BAP1 promotes ferroptosis (a non-apoptotic cell death) through repressing SLC7A11 expression, resulting in tumor suppression

A mTORC1-mediated cyst(e)ine sensing mechanism governing GPX4 synthesis and ferroptosis

Ferroptosis is a cell death mechanism triggered by lipid peroxidation. Our recent study linked cyst(e)ine availability with glutathione peroxidase 4 (GPX4) protein synthesis and ferroptosis mitigation via a Rag-mechanistic target of rapamycin complex 1 (mTORC1) axis, and proposed that co-targeting mTORC1 and ferroptosis is a promising strategy for cancer therapy

Energy stress inhibits ferroptosis via AMPK

Energy stress disturbs cellular homeostasis and induces cell death. Our recent study revealed that ferroptosis (a non-apoptotic cell death) is an energy-requiring process, and energy stress-mediated activation of adenosine monophosphate-activated protein kinase (AMPK) inhibits ferroptosis. Mechanistically, AMPK regulates ferroptosis through acetyl-CoA carboxylase (ACC) and polyunsaturated fatty acid (PUFA) biosynthesis