fnip1

Muscle damage resulting from physical activities such as exercise triggers an immune response crucial for tissue repair and recovery. This study investigates the immune cell profiles in muscle biopsies of individuals engaged in resistance exercise (RE) and explores the impact of age and sex on the immune response following exercise-induced muscle damage. Microarray datasets from muscle biopsies of young and old subjects were analyzed, focusing on the gene expression patterns associated with immune cell activation...

Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been reported to be crucial for the regulation of their activities. However, the structural basis for its regulation and mechanism of its oligomerization are not fully known. Here, we present cryo-EM structures of oligomeric CRL2FEM1B in its unneddylated state, neddylated state in complex with BEX2 as well as neddylated state in complex with FNIP1/FLCN...

Exercise-induced activation of adenosine monophosphate-activated protein kinase (AMPK) and substrate phosphorylation modulate the metabolic capacity of mitochondria in skeletal muscle. However, the key effector(s) of AMPK and the regulatory mechanisms remain unclear. Here, we showed that AMPK phosphorylation of the folliculin interacting protein 1 (FNIP1) serine-220 (S220) controls mitochondrial function and muscle fuel utilization during exercise. Loss of FNIP1 in skeletal muscle resulted in increased mitochondrial content and augmented metabolic capacity, leading to enhanced exercise endurance in mice...

Lysosomes function as critical signaling hubs that govern essential enzyme complexes. LGALS proteins (LGALS3, LGALS8, and LGALS9) are integral to the endomembrane damage response. If ESCRT fails to rectify damage, LGALS-mediated ubiquitination occurs, recruiting autophagy receptors (CALCOCO2, TRIM16, and SQSTM1) and VCP/p97 complex containing UBXN6, PLAA, and YOD1, initiating selective autophagy. Lysosome replenishment through biogenesis is regulated by TFEB. LGALS3 interacts with TFRC and TRIM16, aiding ESCRT-mediated repair and autophagy-mediated removal of damaged lysosomes...

Neurodegenerative diseases (NDs) are characterized by a progressive deterioration of neuronal function, leading to motor and cognitive damage in patients. Astrocytes are essential for maintaining brain homeostasis, and their functional impairment is increasingly recognized as central to the etiology of various NDs. Such impairment can be induced by toxic insults with palmitic acid (PA), a common fatty acid, that disrupts autophagy, increases reactive oxygen species, and triggers inflammation. Although the effects of PA on astrocytes have been addressed, most aspects of the dynamics of this fatty acid remain unknown...

Ischaemia of the heart and limbs attributable to compromised blood supply is a major cause of mortality and morbidity. The mechanisms of functional angiogenesis remain poorly understood, however. Here we show that FNIP1 plays a critical role in controlling skeletal muscle functional angiogenesis, a process pivotal for muscle revascularization during ischemia. Muscle FNIP1 expression is down-regulated by exercise. Genetic overexpression of FNIP1 in myofiber causes limited angiogenesis in mice, whereas its myofiber-specific ablation markedly promotes the formation of functional blood vessels...

Ophiocordyceps gracilis ( O. gracilis ) is a parasitic fungus used in traditional Chinese medicine and functional foods. In this study, a neutral heteropolysaccharide (GSP-1a) was isolated from spores of O. gracilis , and its structure and antioxidant capacities were investigated. GSP-1a was found to have a molecular weight of 72.8 kDa and primarily consisted of mannose (42.28%), galactose (35.7%), and glucose (22.02%). The backbone of GSP-1a was composed of various sugar residues, including →6)-α-D-Manp-(1→, →2,6)-α-D-Manp-(1→, →2,4,6)-α-D-Manp-(1→, →6)-α-D-Glcp-(1→, and →3,6)-α-D-Glcp-(1→, with some branches consisting of →6)-α-D-Manp-(1→ and α-D-Gal-(1→...

MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) orchestrates diverse environmental signals to facilitate cell growth and is frequently activated in cancer. Translocation of MTORC1 from the cytosol to the lysosomal surface by the RRAG GTPases is the key step in MTORC1 activation. Here, we demonstrated that transcription factors MEF2A and MEF2D synergistically regulated MTORC1 activation via modulating its cyto-lysosome shutting. Mechanically, MEF2A and MEF2D controlled the transcription of FNIP1 and FNIP2, the components of the FLCN-FNIP1 or FNIP2 complex that acts as a RRAGC-RRAGD GTPase-activating element to promote the recruitment of MTORC1 to lysosome and its activation...

The AMP-activated protein kinase (AMPK) is known to maintain the integrity of cellular mitochondrial networks by (i) promoting fission, (ii) inhibiting fusion, (iii) promoting recycling of damaged components via mitophagy, (iv) enhancing lysosomal biogenesis to support mitophagy, and (v) promoting biogenesis of new mitochondrial components. While the AMPK targets underlying the first three of these effects are known, a recent paper suggests that direct phosphorylation of the folliculin-interacting protein 1 (FNIP1) by AMPK may be involved in the remaining two...

The diabetic wounds remain to be unsettled clinically, with chronic wounds characterized by drug-resistant bacterial infections, compromised angiogenesis and oxidative damage to the microenvironment. To ameliorate oxidative stress and applying antioxidant treatment in the wound site, we explore the function of folliculin-interacting protein 1 (FNIP1), a mitochondrial gatekeeper protein works to alter mitochondrial morphology, reduce oxidative phosphorylation and protect cells from unwarranted ROS accumulation...

Gastric cancer, as a tumor with poor prognosis, has been widely studied. Distinguishing the types of gastric cancer is helpful. Using the transcriptome data of gastric cancer in our study, relevant proteins of mTOR signaling pathway were screened to identify key genes by four machine learning models, and the models were validated in external datasets. Through correlation analysis, we explored the relationship between five key genes and immune cells and immunotherapy. By inducing cellular senescence in gastric cancer cells with bleomycin, we investigated changes in the expression levels of HRAS through western blot...

Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate-activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)-FNIP1 complex...

Redox homeostasis is essential for keeping our bodies healthy, but it also helps breast cancer cells grow, stay alive, and resist treatment. Changes in the redox balance and problems with redox signaling can make breast cancer cells grow and spread and make them resistant to chemotherapy and radiation therapy. Reactive oxygen species/reactive nitrogen species (ROS/RNS) generation and the oxidant defense system are out of equilibrium, which causes oxidative stress. Many studies have shown that oxidative stress can affect the start and spread of cancer by interfering with redox (reduction-oxidation) signaling and damaging molecules...

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD...

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients...

Heat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function toward client activity in cells remains elusive. Here, we dissect the impact of recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) and Tsc1, toward Hsp90 client activity...

In this issue of Journal of Experimental Medicine, Yin et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20212491) discover that loss of FNIP1 is associated with browning of white adipose tissue, which they propose is driven by decreased calcium uptake into the ER.

Metabolically beneficial beige adipocytes offer tremendous potential to combat metabolic diseases. The folliculin interacting protein 1 (FNIP1) is implicated in controlling cellular metabolism via AMPK and mTORC1. However, whether and how FNIP1 regulates adipocyte browning is unclear. Here, we demonstrate that FNIP1 plays a critical role in controlling adipocyte browning and systemic glucose homeostasis. Adipocyte-specific ablation of FNIP1 promotes a broad thermogenic remodeling of adipocytes, including increased UCP1 levels, high mitochondrial content, and augmented capacity for mitochondrial respiration...

Proteolysis-targeting chimeras (PROTACs), heterobifunctional compounds that consist of protein-targeting ligands linked to an E3 ligase recruiter, have arisen as a powerful therapeutic modality for targeted protein degradation (TPD). Despite the popularity of TPD approaches in drug discovery, only a small number of E3 ligase recruiters are available for the >600 E3 ligases that exist in human cells. Here, we have discovered a cysteine-reactive covalent ligand, EN106, that targets FEM1B, an E3 ligase recently discovered as the critical component of the cellular response to reductive stress...

The Hsp90 molecular chaperone, along with a set of approximately 50 cochaperones, mediates the folding and activation of hundreds of cellular proteins in an ATP-dependent cycle. Cochaperones differ in how they interact with Hsp90 and their ability to modulate ATPase activity of Hsp90. Cochaperones often compete for the same binding site on Hsp90, and changes in levels of cochaperone expression that occur during neurodegeneration, cancer, or aging may result in altered Hsp90-cochaperone complexes and client activity...