Understanding of the evolution of metazoans from their unicellular ancestors is a fundamental question in biology. In contrast to fungi which utilize the Mon1-Ccz1 dimeric complex to activate the small GTPase RAB7A, metazoans rely on the Mon1-Ccz1-RMC1 trimeric complex. Here, we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex. RMC1 acts as a scaffolding subunit and binds to both Mon1 and Ccz1 on the surface opposite to the RAB7A-binding site, with many of the RMC1-contacting residues from Mon1 and Ccz1 unique to metazoans, explaining the binding specificity. Significantly, the assembly of RMC1 with Mon1-Ccz1 is required for cellular RAB7A activation, autophagic functions and organismal development in zebrafish. Our studies offer a molecular explanation for the different degree of subunit conservation across species, and provide an excellent example of how metazoan-specific proteins take over existing functions in unicellular organisms.

Cryo-EM structure of the Mon1-Ccz1-RMC1 complex reveals molecular basis of metazoan RAB7A activation.

Puerarin attenuates valproate-induced features of ASD in male mice via regulating Slc7a11-dependent ferroptosis.

<h2>Abstract</h2> CD36, a scavenger receptor B2 that is dynamically distributed between cell membranes and organelle membranes, plays a crucial role in regulating lipid metabolism. Abnormal CD36 activity has been linked to a range of metabolic disorders, such as obesity, nonalcoholic fatty liver disease, insulin resistance and cardiovascular disease. CD36 undergoes various modifications, including palmitoylation, glycosylation, and ubiquitination, which greatly affect its binding affinity to various ligands, thereby triggering and influencing various biological effects. In the context of tumors, CD36 interacts with autophagy to jointly regulate tumorigenesis, mainly by influencing the tumor microenvironment. The central role of CD36 in cellular lipid homeostasis and recent molecular insights into CD36 in tumor development indicate the applicability of CD36 as a therapeutic target for cancer treatment. Here, we discuss the diverse posttranslational modifications of CD36 and their respective roles in lipid metabolism. Additionally, we delve into recent research findings on CD36 in tumors, outlining ongoing drug development efforts targeting CD36 and potential strategies for future development and highlighting the interplay between CD36 and autophagy in the context of cancer. Our aim is to provide a comprehensive understanding of the function of CD36 in both physiological and pathological processes, facilitating a more in-depth analysis of cancer progression and a better development and application of CD36-targeting drugs for tumor therapy in the near future. 

Interplay of CD36, autophagy, and lipid metabolism: insights into cancer progression

Abstract Liver kinase B1 (LKB1), an evolutionarily conserved serine/threonine kinase, is a master regulator of the AMPK subfamily and controls cellular events such as polarity, proliferation, and energy homeostasis. Functions and mechanisms of the LKB1-AMPK axis at specific subcellular compartments, such as lysosome and mitochondria, have been established. AMPK is known to be activated at the Golgi; however, functions and regulatory mechanisms of the LKB1-AMPK axis at the Golgi apparatus remain elusive. Here, we show that TBC1D23, a Golgi-localized protein that is frequently mutated in the neurodevelopment disorder pontocerebellar hypoplasia (PCH), is specifically required for the LKB1 signaling at the Golgi. TBC1D23 directly interacts with LKB1 and recruits LKB1 to Golgi, promoting Golgi-specific activation of AMPK upon energy stress. Notably, Golgi-targeted expression of LKB1 rescues TBC1D23 deficiency in zebrafish models. Furthermore, the loss of LKB1 causes neurodevelopmental abnormalities in zebrafish, which partially recapitulates defects in TBC1D23-deficient zebrafish, and LKB1 sustains normal neuronal development via TBC1D23 interaction. Our study uncovers a regulatory mechanism of the LKB1 signaling, and reveals that a disrupted Golgi-LKB1 signaling underlies the pathogenesis of PCH. 

TBC1D23 mediates Golgi-specific LKB1 signaling

ABSTRACT Probiotics can effectively improve a variety of neurological diseases, but there is little research on autism, and the specific mechanism is unclear. In this study, shotgun metagenomics analysis was used to investigate the preventive and therapeutic effects of Bifidobacterium animalis subsp. lactis Probio-M8 on autism. The results showed that Probio-M8 treatment significantly alleviated valproate (VPA)-induced autism in mice, with autistic symptoms characterized by increased stereotyped behaviors such as grooming, reduced learning ability, and decreased desire to socialize. Further studies have found that Probio-M8 can alleviate autism by optimizing gut microbiota diversity and regulating metabolic levels. Probio-M8 regulates gut microbiota structure by increasing the abundance of beneficial bacteria such as Bifidobacterium globosum and Akkermansia muciniphila. In addition, Probio-M8 regulates metabolic activity by increasing levels of choline, which corrects CAZy disorders. In conclusion, Probio-M8 is therapeutic in the VPA-induced autism mouse model by regulating the gut microbiome and metabolic levels. IMPORTANCE Individuals with autism often exhibit symptoms of social invariance, obsessive-compulsive tendencies, and repetitive behaviors. However, early intervention and treatment can be effective in improving social skills and mitigating autism symptoms, including behaviors related to irritability. Although taking medication for autism may lead to side effects such as weight gain, probiotics can be an ideal intervention for alleviating these symptoms. In this study, we investigated the effects of Probio-M8 intervention on the behavior of autistic mice using an open-field test, a three-chamber sociability test, and a novel object recognition test. Metagenomic analysis revealed differences in gut microbiota diversity among groups, predicted changes in metabolite levels, and functionally annotated CAZy. Additionally, we analyzed serum neurotransmitter levels and found that probiotics were beneficial in mitigating neurotransmitter imbalances in mice with autism. Individuals with autism often exhibit symptoms of social invariance, obsessive-compulsive tendencies, and repetitive behaviors. However, early intervention and treatment can be effective in improving social skills and mitigating autism symptoms, including behaviors related to irritability. Although taking medication for autism may lead to side effects such as weight gain, probiotics can be an ideal intervention for alleviating these symptoms. In this study, we investigated the effects of Probio-M8 intervention on the behavior of autistic mice using an open-field test, a three-chamber sociability test, and a novel object recognition test. Metagenomic analysis revealed differences in gut microbiota diversity among groups, predicted changes in metabolite levels, and functionally annotated CAZy. Additionally, we analyzed serum neurotransmitter levels and found that probiotics were beneficial in mitigating neurotransmitter imbalances in mice with autism.

Bifidobacterium animalis subsp. lactis Probio-M8 alleviates abnormal behavior and regulates gut microbiota in a mouse model suffering from autism

Macroautophagy/autophagy plays a protective role in sepsis-induced liver injury. As a member of class B scavenger receptors, CD36 plays important roles in various disorders, such as atherosclerosis and fatty liver disease. Here we found that the expression of CD36 in hepatocytes was increased in patients and a mouse model with sepsis, accompanied by impaired autophagy flux. Furthermore, hepatocyte cd36 knockout (cd36-HKO) markedly improved liver injury and the impairment of autophagosome-lysosome fusion in lipopolysaccharide (LPS)-induced septic mice. Ubqln1 (ubiquilin 1) overexpression (OE) in hepatocyte blocked the protective effect of cd36-HKO on LPS-induced liver injury in mice. Mechanistically, with LPS stimulation, CD36 on the plasma membrane was depalmitoylated and distributed to the lysosome, where CD36 acted as a bridge molecule linking UBQLN1 to soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and hence promoting the proteasomal degradation of SNARE proteins, resulting in fusion impairment. Overall, our data reveal that CD36 is essential for modulating the proteasomal degradation of autophagic SNARE proteins in a UBQLN1-dependent manner. Targeting CD36 in hepatocytes is effective for improving autophagic flux in sepsis and therefore represents a promising therapeutic strategy for clinical treatment of septic liver injury.

Hepatocyte CD36 modulates UBQLN1-mediated proteasomal degradation of autophagic SNARE proteins contributing to septic liver injury.

Abstract Autism spectrum disorder (ASD) affects 1–2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin ( SCGN ), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN , and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success. 

/pdf/scgn-deficiency-is-a-risk-factor-for-autism-spectrum-cnkrtbkr.pdf

SCGN deficiency is a risk factor for autism spectrum disorder

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Hepatocyte CD36 modulates UBQLN1-mediated proteasomal degradation of autophagic SNARE proteins contributing to septic liver injury.

SCGN deficiency is a risk factor for autism spectrum disorder