Biochemical Journal最新文献

Nephrin is a transmembrane Ig-like domain-containing protein that serves as a central structural and signaling scaffold in kidney filtration. First identified in 1998 as mutated in congenital nephrotic syndrome, the recent identification of nephrin autoantibodies in acquired kidney diseases has sparked renewed interest in nephrin biology. In specialized cells known as podocytes, nephrin helps establish and maintain the slit diaphragm (SD), a unique cell-cell junction formed between interdigitating cell projections known as foot processes (FPs). Together, the SD and FP are among the first stages of renal filtration, where they are subject to numerous biochemical and mechanical stressors. Although podocytes are highly adapted to this environment, over time and with injury, this elevated strain can lead to pathological structural changes, detachment, and proteinuria. As such, the complex set of signaling mechanisms provided by nephrin are essential for controlling podocyte adaptability. Herein, we provide a thorough and up-to-date review on nephrin signaling, including a focus on cross-talk between nephrin interactors and signaling regions across podocytes. We first highlight new findings regarding podocyte structure and function, followed by an emphasis on why nephrin is among the most critical proteins for maintaining these features. We then detail a comprehensive list of known nephrin interactors and describe several of their effects, including calcium regulation, cell survival, cell polarity, phase separation-mediated actin reorganization, and SD-focal adhesion dynamics. Collectively, our emerging understanding of the broader cellular context of nephrin signaling provides important insight for clinical strategies to mitigate podocyte injury and kidney disease progression.

Leucine-rich repeat kinase 2 (LRRK2) has emerged as a promising therapeutic target for the treatment of neurodegenerative Parkinson's disease (PD). Data from a multitude of pre-clinical models are supportive of a potential role for LRRK2 therapies to ameliorate cellular dysfunctions found in PD, and small molecules to inhibit LRRK2 kinase activity, as well as antisense oligonucleotides to target the protein itself, are in clinical trials. Despite this, exactly how LRRK2 contributes to PD pathogenesis remains to be determined, and definitive biomarkers to track LRRK2 function are still required. Such biomarkers can be useful for monitoring the pharmacodynamic response of LRRK2 therapeutics and/or understanding the relationship between LRRK2 and the clinical progression of PD. Moreover, biomarkers that can identify increased LRRK2 levels or activity beyond just carriers of pathogenic LRRK2 mutations will be important for expanding LRRK2 therapeutics to other PD populations. This review summarizes recent findings regarding biomarkers of LRRK2.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, rigidity, and bradykinesia as well as degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). A minority of PD cases are familial and are caused by a single genetic mutation. One of the most common PD-causing genes is leucine-rich repeat kinase 2 (LRRK2), which causes an autosomal dominant PD that presents very similarly to sporadic PD. Pathogenic mutations in LRRK2 increase its kinase activity, indicated by both LRRK2 autophosphorylation and phosphorylation of its substrates. To date, the mechanism(s) by which elevated LRRK2 kinase activity induces DA neuron degeneration and PD has not been fully elucidated. One potential mechanism may involve the role of LRRK2 on mitochondria, as mitochondrial dysfunction has been linked to PD pathogenesis, and exciting recent evidence has connected PD pathogenic mutations in LRRK2 to multiple aspects of mitochondrial dysfunction associated with the disease. In this review, we discuss the current knowledge implicating LRRK2 in mitochondrial energetics, oxidative stress, genome integrity, fission/fusion, mitophagy, and ion/protein transport in PD, as well as examine the potential role LRRK2 may play in mediating the effects of mitochondrial therapeutics being investigated for treatment of PD.

Cancers have traditionally been classified based on their tissue of origin. However, with advances in sophisticated genome sequencing techniques and progression toward an era of precision medicine, it has become increasingly clear that classifying tumors based on unifying molecular features instead of tissue of origin may hold the key to improving patient outcomes. Various efforts have been undertaken to address this critical aspect of cancer biology, but it is still unclear as to the best approach to stratify tumors into different molecular classes. One approach is to define many small subclasses based on complex molecular signatures, while another option is to divide cancers into larger groups based on higher-order features of cancer behavior. This latter approach holds appeal as it may provide opportunities to identify broadly relevant therapeutics. However, our understanding of these fundamental 'rules' of cancer biology and how they can be used to better classify and treat cancers is in its infancy. We recently demonstrated that cancers can be functionally stratified into binary YAPon and YAPoff super-classes with unique therapeutic vulnerabilities based on distinct expression and function of the transcriptional coactivators, YAP and TAZ. In YAPon cancers, YAP and TAZ drive oncogenesis, whereas in YAPoff cancers, YAP and TAZ are instead tumor suppressors. In this review, we discuss our understanding of these distinct cancer classes with a focus on the mechanisms that underlie the opposite function of YAP/TAZ in YAPon and YAPoff cancers, as well as the potential therapeutic implications of these findings.

The adaptor protein, speckle-type BTB/POZ protein (SPOP), recruits substrates to the cullin-3-subclass of E3 ligase for selective protein ubiquitylation. The Myddosome protein, myeloid differentiation primary response 88 (MyD88), is ubiquitylated by the SPOP-based E3 ligase to negatively regulate immune signaling; however, the sequence rules for SPOP-mediated substrate engagement and degradation are not fully understood. Here, we show that MyD88 interacts with SPOP through a long degron that contains the established SPOP-binding consensus and an N-terminal site that we name the Q-motif. Based on the sequence similarity to MyD88, we show that additional substrates, including steroid receptor coactivator-3, SET domain-containing protein 2, and Caprin1, engage SPOP in this manner. We show that the Q-motif is a critical determinant of these interactions in mammalian cells and determine X-ray crystal structures that show the molecular basis of SPOP associations with these proteins. These studies reveal a new consensus sequence for substrate-binding to SPOP that is necessary for substrate ubiquitylation, thus expanding the sequence rules required for SPOP-mediated E3 ligase substrate recognition.