In silico analysis and functional characterization of a leucine-rich repeat protein of Leptospira interrogans.

Pathogenic spirochetes of the genus Leptospira are the causative agent of leptospirosis, a widely disseminated zoonosis that affects humans and animals. The ability of leptospires to quickly cross host barriers causing infection is not yet fully understood. Thus, understanding the mechanisms of pathogenicity is important to combat leptospiral infection. Outer membrane proteins are interesting targets to study as they are able to interact with host molecules. Proteins containing leucine-rich repeat (LRR) domains are characterized by the presence of multiple regions containing leucine residues and they have putative functions related to host-pathogen interactions. Hence, the present study aimed to clone and express the recombinant protein encoded by the LIC11098 gene, an LRR protein of L. interrogans serovar Copenhageni. In silico analyses predicted that the target protein is conserved among pathogenic strains of Leptospira, having a signal peptide and multiple LRR domains. The DNA sequence encoding the LRR protein was cloned in frame into the pAE vector, expressed without mutations in Escherichia coli and purified by His-tag chromatography. Circular dichroism (CD) spectrum showed that the recombinant protein was predominantly composed of ß-sheets. A dose-dependent interaction was observed with cellular and plasma fibronectins, laminin and the complement system component C9, suggesting a possible role of the protein encoded by LIC11098 gene at the initial stages of infection.

Variations in the LINGO2 and GLIS3 Genes and Gene-Environment Interactions Increase Gestational Diabetes Mellitus Risk in Chinese Women.

Gestational diabetes mellitus (GDM) has been found to be a common complication in pregnant women, known to escalate the risk of negative obstetric outcomes. In our study, we genotyped 1,566 Chinese pregnant women for two single nucleotide polymorphisms (SNPs) in the LINGO2 gene and one SNP in the GLIS3 gene, utilizing targeted next-generation sequencing. The impact of two interacting genes, and the interaction of genes with the environment─including exposure to particulate matter (PM2.5), ozone (O3), and variations in prepregnancy body mass index (BMI)─on the incidence of GDM were analyzed using logistic regression. Our findings identify the variants LINGO2 rs10968576 (P = 0.022, OR = 1.224) and rs1412239 (P = 0.018, OR = 1.231), as well as GLIS3 rs10814916 (P = 0.028, OR = 1.172), as risk mutations significantly linked to increased susceptibility to GDM. Further analysis underscores the crucial role of gene-gene and gene-environment interactions in the development of GDM among Chinese women (P < 0.05). Particularly, the individuals carrying the rs10968576 G-rs1412239 G-rs10814916 C haplotype exhibit increased susceptibility to GDM during the prepregnancy period when interacting with PM2.5, O3, and BMI (P = 8.004 × 10-7, OR = 1.206; P = 6.3264 × 10-11, OR = 1.280; P = 9.928 × 10-7, OR = 1.334, respectively). In conclusion, our research emphasizes the importance of the interaction between specific gene variations─LINGO2 and GLIS3─and environmental factors in influencing GDM risk. Notably, we found significant associations between these gene variations and GDM risk across various environmental exposure periods.

Expression analysis of genes encoding extracellular leucine-rich repeat proteins in Arabidopsis thaliana.

Leucine-rich repeat (LRR)-containing proteins have been identified in diverse species, including plants. The diverse intracellular and extracellular LRR variants are responsible for numerous biological processes. We analyzed the expression patterns of Arabidopsis thaliana extracellular LRR (AtExLRR) genes, 10 receptor-like proteins, and 4 additional genes expressing the LRR-containing protein by a promoter: ß-glucuronidase (GUS) study. According to in silico expression studies, several AtExLRR genes were expressed in a tissue- or stage-specific and abiotic/hormone stress-responsive manner, indicating their potential participation in specific biological processes. Based on the promoter: GUS assay, AtExLRRs were expressed in different cells and organs. A quantitative real-time PCR investigation revealed that the expressions of AtExLRR3 and AtExLRR9 were distinct under various abiotic stress conditions. This study investigated the potential roles of extracellular LRR proteins in plant growth, development, and response to various abiotic stresses.

Leucine-Rich Repeat in Polycystin-1 Suppresses Cystogenesis in a Zebrafish (Danio rerio) Model of Autosomal-Dominant Polycystic Kidney Disease.

Mutations of PKD1 coding for polycystin-1 (PC1) account for most cases of autosomal-dominant polycystic kidney disease (ADPKD). The extracellular region of PC1 contains many evolutionarily conserved domains for ligand interactions. Among these are the leucine-rich repeats (LRRs) in the far N-terminus of PC1. Using zebrafish (Danio rerio) as an in vivo model system, we explored the role of LRRs in the function of PC1. Zebrafish expresses two human PKD1 paralogs, pkd1a and pkd1b. Knockdown of both genes in zebrafish by morpholino antisense oligonucleotides produced phenotypes of dorsal-axis curvature and pronephric cyst formation. We found that overexpression of LRRs suppressed both phenotypes in pkd1-morphant zebrafish. Purified recombinant LRR domain inhibited proliferation of HEK cells in culture and interacted with the heterotrimeric basement membrane protein laminin-511 (α5ß1γ1) in vitro. Mutations of amino acid residues in LRRs structurally predicted to bind laminin-511 disrupted LRR-laminin interaction in vitro and neutralized the ability of LRRs to inhibit cell proliferation and cystogenesis. Our data support the hypothesis that the extracellular region of PC1 plays a role in modulating PC1 interaction with the extracellular matrix and contributes to cystogenesis of PC1 deficiency.

Unusual structural and functional features of TpLRR/BspA-like LRR proteins.

Leucine Rich Repeat (LRR) domains, are present in hundreds of thousands of proteins across all kingdoms of life and are typically involved in protein-protein interactions and ligand recognition. LRR domains are classified into eight classes and when examined in three dimensions seven, of them form curved solenoid-like super-helices, also described as toruses, with a beta sheet on the concave (inside) and stacked alpha-helices on the convex (outside) of the torus. Here we present an overview of the least characterized 8th class of LRR proteins, the TpLRR-like LRRs, named after the Treponema pallidum protein Tp0225. Proteins from the TpLRR class differ from the proteins in all other known LRR classes by having a flipped curvature, with the beta sheet on the convex side of the torus and irregular secondary structure instead of helices on the opposite, now concave site. TpLRR proteins also present highly divergent sequence pattern of individual repeats and can associate with specific types of additional domains. Several of the characterized proteins from this class, specifically the BspA-like proteins, were found in human bacterial and protozoan pathogens, playing an important role in the interactions between the pathogens and the host immune system. In this paper we surveyed all existing experimental structures and selected AlphaFold models of the best-known proteins containing this class of LRR repeats, analyzing the relation between the pattern of conserved residues, specific structural features and functions of these proteins.

Nucleotide-binding leucine-rich repeat network underlies nonhost resistance of pepper against the Irish potato famine pathogen Phytophthora infestans.

Nonhost resistance (NHR) is a robust plant immune response against non-adapted pathogens. A number of nucleotide-binding leucine-rich repeat (NLR) proteins that recognize non-adapted pathogens have been identified, although the underlying molecular mechanisms driving robustness of NHR are still unknown. Here, we screened 57 effectors of the potato late blight pathogen Phytophthora infestans in nonhost pepper (Capsicum annuum) to identify avirulence effector candidates. Selected effectors were tested against 436 genome-wide cloned pepper NLRs, and we identified multiple functional NLRs that recognize P. infestans effectors and confer disease resistance in the Nicotiana benthamiana as a surrogate system. The identified NLRs were homologous to known NLRs derived from wild potatoes that recognize P. infestans effectors such as Avr2, Avrblb1, Avrblb2, and Avrvnt1. The identified CaRpi-blb2 is a homologue of Rpi-blb2, recognizes Avrblb2 family effectors, exhibits feature of lineage-specifically evolved gene in microsynteny and phylogenetic analyses, and requires pepper-specific NRC (NLR required for cell death)-type helper NLR for proper function. Moreover, CaRpi-blb2-mediated hypersensitive response and blight resistance were more tolerant to suppression by the PITG_15 278 than those mediated by Rpi-blb2. Combined results indicate that pepper has stacked multiple NLRs recognizing effectors of non-adapted P. infestans, and these NLRs could be more tolerant to pathogen-mediated immune suppression than NLRs derived from the host plants. Our study suggests that NLRs derived from nonhost plants have potential as untapped resources to develop crops with durable resistance against fast-evolving pathogens by stacking the network of nonhost NLRs into susceptible host plants.

Polycistronic baculovirus expression of SUGT1 enables high-yield production of recombinant leucine-rich repeat proteins and protein complexes.

The SHOC2-MRAS-PPP1CA (SMP) complex is a holoenzyme that plays a vital role in the MAP kinase signaling pathway. Previous attempts to produce this challenging three-protein complex have relied on co-infection with multiple viruses and the use of affinity tags to attempt to isolate functional recombinant protein complexes. Leucine-rich repeat containing proteins have been historically challenging to express, and we hypothesized that co-expression of appropriate chaperones may be necessary for optimal production. We describe here how the SUGT1 chaperone can, in conjunction with polycistronic protein expression in baculovirus-infected insect cells, dramatically enhance production yield and quality of recombinant SHOC2, the SMP complex, and other leucine-rich repeat proteins.

Cytoplasmic and nuclear Sw-5b NLR act both independently and synergistically to confer full host defense against tospovirus infection.

Plant intracellular nucleotide-binding leucine-rich repeat (NLR) receptors play critical roles in mediating host immunity to pathogen attack. We use tomato Sw-5b::tospovirus as a model system to study the specific role of the compartmentalized plant NLR in dictating host defenses against the virus at different infection steps. We demonstrated here that tomato NLR Sw-5b distributes to the cytoplasm and nucleus, respectively, to play different roles in inducing host resistances against tomato spotted wilt orthotospovirus (TSWV) infection. The cytoplasmic-enriched Sw-5b induces a strong cell death response to inhibit TSWV replication. This host response is, however, insufficient to block viral intercellular and long-distance movement. The nuclear-enriched Sw-5b triggers a host defense that weakly inhibits viral replication but strongly impedes virus intercellular and systemic movement. Furthermore, the cytoplasmic and nuclear Sw-5b act synergistically to dictate a full host defense of TSWV infection. We further demonstrated that the extended N-terminal Solanaceae domain (SD) of Sw-5b plays critical roles in cytoplasm/nucleus partitioning. Sw-5b NLR controls its cytoplasm localization. Strikingly, the SD but not coil-coil domain is crucial for Sw-5b receptor to import into the nucleus to trigger the immunity. The SD was found to interact with importins. Silencing both importin α and ß expression disrupted Sw-5b nucleus import and host immunity against TSWV systemic infection. Collectively, our findings suggest that Sw-5b bifurcates disease resistances by cytoplasm/nucleus partitioning to block different infection steps of TSWV. The findings also identified a new regulatory role of extra domain of a plant NLR in mediating host innate immunity.

Aryl Hydrocarbon Receptor Defect Attenuates Mitogen-Activated Signaling through Leucine-Rich Repeats and Immunoglobulin-like Domains 1 (LRIG1)-Dependent EGFR Degradation.

Aryl hydrocarbon receptor (AHR) genomic pathway has been well-characterized in a number of respiratory diseases. In addition, the cytoplasmic AHR protein may act as an adaptor of E3 ubiquitin ligase. In this study, the physiological functions of AHR that regulate cell proliferation were explored using the CRISPR/Cas9 system. The doubling-time of the AHR-KO clones of A549 and BEAS-2B was observed to be prolonged. The attenuation of proliferation potential was strongly associated with either the induction of p27Kip1 or the impairment in mitogenic signal transduction driven by the epidermal growth factor (EGF) and EGF receptor (EGFR). We found that the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a repressor of EGFR, was induced in the absence of AHR in vitro and in vivo. The LRIG1 tends to degrade via a proteasome dependent manner by interacting with AHR in wild-type cells. Either LRIG1 or a disintegrin and metalloprotease 17 (ADAM17) were accumulated in AHR-defective cells, consequently accelerating the degradation of EGFR, and attenuating the response to mitogenic stimulation. We also affirmed low AHR but high LRIG1 levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients. This might partially elucidate the sluggish tissue repairment and developing inflammation in COPD patients.

Effect of extensin-like OsPEX1 on pollen fertility in rice.

LRXs (leucine-rich repeat extensins) are chimeric cell wall proteins containing an N-terminal leucine-rich repeat (LRR) and a C-terminal extensin domain. Increasing evidences suggest that LRXs family genes play important roles in pollen germination and pollen tube growth in Arabidopsis thaliana. However, the functions of rice (Oryza sativa L.) LRX genes in pollen development remain poorly understood. Bioinformatics analysis showed that the rice LRX gene family consist of eight members, namely OsPEX3, OsLRX3 and OsLRX5 located on chromosome 1, OsLRX1, OsLRX3, OsLRX2,OsPEX1 and OsPEX2 located on chromosome 2, 5, 6, 11 and 12, respectively. The OsPEX1 gene is preferentially expressed in rice anther, suggesting that it may be involved in the regulation of pollen development. Next, we further investigated the role of the OsPEX1 gene in rice by knockdown of its expression using an RNAi approach. The OsPEX1 RNAi transgenic lines showed a significant decrease in seed setting rate (10%~30%) due to pollen sterility. Further quantitative RT-PCR analysis indicated that the OsPEX1 gene was significantly down-regulated in the RNAi transgenic lines. The results indicate that the OsPEX1plays an important role in the regulation of rice pollen development. Further studies on this gene could provide insights on the molecular and genetic mechanisms in this developmental process.

Inhibition of leucine-rich repeats and calponin homology domain containing 1 accelerates microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model.

BACKGROUND: Spinal cord injury (SCI) triggers the primary mechanical injury and secondary inflammation-mediated injury. Neuroinflammation-mediated insult causes secondary and extensive neurological damage after SCI. Microglia play a pivotal role in the initiation and progression of post-SCI neuroinflammation. METHODS: To elucidate the significance of LRCH1 to microglial functions, we applied lentivirus-induced LRCH1 knockdown in primary microglia culture and tested the role of LRCH1 in microglia-mediated inflammatory reaction both in vitro and in a rat SCI model. RESULTS: We found that LRCH1 was downregulated in microglia after traumatic SCI. LRCH1 knockdown increased the production of pro-inflammatory cytokines such as IL-1ß, TNF-α, and IL-6 after in vitro priming with lipopolysaccharide and adenosine triphosphate. Furthermore, LRCH1 knockdown promoted the priming-induced microglial polarization towards the pro-inflammatory inducible nitric oxide synthase (iNOS)-expressing microglia. LRCH1 knockdown also enhanced microglia-mediated N27 neuron death after priming. Further analysis revealed that LRCH1 knockdown increased priming-induced activation of p38 mitogen-activated protein kinase (MAPK) and Erk1/2 signaling, which are crucial to the inflammatory response of microglia. When LRCH1-knockdown microglia were adoptively injected into rat spinal cords, they enhanced post-SCI production of pro-inflammatory cytokines, increased SCI-induced recruitment of leukocytes, aggravated SCI-induced tissue damage and neuronal death, and worsened the locomotor function. CONCLUSION: Our study reveals for the first time that LRCH1 serves as a negative regulator of microglia-mediated neuroinflammation after SCI and provides clues for developing novel therapeutic approaches against SCI.

Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy.

Leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) is an endogenous feedback regulator of receptor tyrosine kinases (RTKs) and was recently shown to inhibit growth of different types of malignancies. Additionally, this multifaceted RTK inhibitor was reported to be a tumor suppressor, a stem cell regulator, and a modulator of different cellular phenotypes. This mini-review provides a concise and up-to-date summary about the known functions of LRIG1 and its related family members, with a special emphasis on underlying molecular mechanisms and the opportunities for harnessing its therapeutic potential against cancer.

Genomic and Molecular Perspectives of Host-pathogen Interaction and Resistance Strategies against White Rust in Oilseed Mustard.

Oilseed brassicas stand as the second most valuable source of vegetable oil and the third most traded one across the globe. However, the yield can be severely affected by infections caused by phytopathogens. White rust is a major oomycete disease of oilseed brassicas resulting in up to 60% yield loss globally. So far, success in the development of oomycete resistant Brassicas through conventional breeding has been limited. Hence, there is an imperative need to blend conventional and frontier biotechnological means to breed for improved crop protection and yield. This review provides a deep insight into the white rust disease and explains the oomycete-plant molecular events with special reference to Albugo candida describing the role of effector molecules, A. candida secretome, and disease response mechanism along with nucleotide-binding leucine-rich repeat receptor (NLR) signaling. Based on these facts, we further discussed the recent progress and future scopes of genomic approaches to transfer white rust resistance in the susceptible varieties of oilseed brassicas, while elucidating the role of resistance and susceptibility genes. Novel genomic technologies have been widely used in crop sustainability by deploying resistance in the host. Enrichment of NLR repertoire, over-expression of R genes, silencing of avirulent and disease susceptibility genes through RNA interference and CRSPR-Cas are technologies which have been successfully applied against pathogen-resistance mechanism. The article provides new insight into Albugo and Brassica genomics which could be useful for producing high yielding and WR resistant oilseed cultivars across the globe.

LncRNA-PCAT-1 promotes non-small cell lung cancer progression by regulating miR-149-5p/LRIG2 axis.

Long noncoding RNAs (lncRNAs) are key players in the development and progression of human cancers. The lncRNA PCAT-1 has been shown to be upregulated in human non-small cell lung cancer (NSCLC); however, its role and molecular mechanisms in NSCLC cell progression remain unclear. Here, we found that the higher expression of PCAT-1 led to a significantly poorer survival time, and multivariate analysis revealed that PCAT-1 was an independent risk factor of prognosis in NSCLC. Furthermore, we also found that the knockdown of PCAT-1 remarkably suppressed cell growth by inducing cell cycle arrest and apoptosis promotion in NSCLC cells. Moreover, the bioinformatics analysis and luciferase reporter assay revealed that PCAT-1 directly bound to the miR-149-5p, which has been reported to act as a tumor suppressor in diverse cancers. In addition, our results confirmed that the tumor-promoting effects of PCAT-1 in NSCLC cells are at least partly through negative modulation of miR-149-5p. Finally, mechanistic investigations showed that PCAT-1 upregulated the expression of miR-149-5p target gene leucine-rich repeats and immunoglobulin (Ig)-like domains 2 (LRIG2) through competitively "spongeing" miR-149-5p. Therefore, we concluded that PCAT-1 may promote the development of NSCLC through the miR-149-5p/LRIG2 axis.

Downregulation of leucine-rich repeats and immunoglobulin-like domains 1 by microRNA-20a modulates gastric cancer multidrug resistance.

Multidrug resistance (MDR) significantly restricts the clinical efficacy of gastric cancer (GC) chemotherapy, and it is critical to search novel targets to predict and overcome MDR. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) has been proved to be correlated with drug resistance in several cancers. The present study revealed that LRIG1 was overexpressed in chemosensitive GC tissues and decreased expression of LRIG1 predicted poor survival in GC patients. We observed that upregulation of LRIG1 enhanced chemosensitivity in GC cells. Interestingly, miR-20a, which was overexpressed in GC MDR cell lines and tissues, was identified to regulate LRIG1 expression by directly targeting its 3' untranslated region. We also found that inhibition of miR-20a suppressed GC MDR, and upregulation showed opposite effects. Moreover, we demonstrated that the miR-20a/LRIG1 axis regulated GC cell MDR through epidermal growth factor receptor (EGFR)-mediated PI3K/AKT and MAPK/ERK signaling pathways. Finally, LRIG1 expression in human GC tissues is inversely correlated with miR-20a and EGFR. Taken together, the newly identified miR-20a/LRIG1/EGFR link provides insight into the MDR process of GC, and targeting this axis represents a novel potential therapeutic strategy to block GC chemoresistance.

Plant STAND P-loop NTPases: a current perspective of genome distribution, evolution, and function : Plant STAND P-loop NTPases: genomic organization, evolution, and molecular mechanism models contribute broadly to plant pathogen defense.

STAND P-loop NTPase is the common weapon used by plant and other organisms from all three kingdoms of life to defend themselves against pathogen invasion. The purpose of this study is to review comprehensively the latest finding of plant STAND P-loop NTPase related to their genomic distribution, evolution, and their mechanism of action. Earlier, the plant STAND P-loop NTPase known to be comprised of only NBS-LRRs/AP-ATPase/NB-ARC ATPase. However, recent finding suggests that genome of early green plants comprised of two types of STAND P-loop NTPases: (1) mammalian NACHT NTPases and (2) NBS-LRRs. Moreover, YchF (unconventional G protein and members of P-loop NTPase) subfamily has been reported to be exceptionally involved in biotic stress (in case of Oryza sativa), thereby a novel member of STAND P-loop NTPase in green plants. The lineage-specific expansion and genome duplication events are responsible for abundance of plant STAND P-loop NTPases; where "moderate tandem and low segmental duplication" trajectory followed in majority of plant species with few exception (equal contribution of tandem and segmental duplication). Since the past decades, systematic research is being investigated into NBS-LRR function supported the direct recognition of pathogen or pathogen effectors by the latest models proposed via 'integrated decoy' or 'sensor domains' model. Here, we integrate the recently published findings together with the previous literature on the genomic distribution, evolution, and distinct models proposed for functional molecular mechanism of plant STAND P-loop NTPases.

Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice.

Genetic factors confer risk for cardiovascular disease. Recently, large genome-wide population studies have shown associations between genomic loci close to LRIG3 and heart failure and plasma high-density lipoprotein (HDL) cholesterol level. Here, we ablated Lrig3 in mice and investigated the importance of Lrig3 for heart function and plasma lipid levels. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze Lrig3 expression in the hearts of wild-type and Lrig3-deficient mice. In addition, molecular, physiological, and functional parameters such as organ weights, heart rate, blood pressure, heart structure and function, gene expression in the heart, and plasma insulin, glucose, and lipid levels were evaluated. The Lrig3-deficient mice were smaller than the wild-type mice but otherwise appeared grossly normal. Lrig3 was expressed at detectable but relatively low levels in adult mouse hearts. At 9 mo of age, ad libitum-fed Lrig3-deficient mice had lower insulin levels than wild-type mice. At 12 mo of age, Lrig3-deficient mice exhibited increased blood pressure, and the Lrig3-deficient female mice displayed signs of cardiac hypertrophy as assessed by echocardiography, heart-to-body weight ratio, and expression of the cardiac hypertrophy marker gene Nppa. Additionally, Lrig3-deficient mice had reduced plasma HDL cholesterol and free glycerol. These findings in mice complement the human epidemiological results and suggest that Lrig3 may influence heart function and plasma lipid levels in mice and humans.

Identification and expressional analysis of NLRC5 inflammasome gene in smolting Atlantic salmon (Salmo salar).

The NOD-like receptors (NLRs) were recently identified as an intracellular pathogen recognition receptor family in vertebrates. While the immune system participation of NLRs has been characterized and analyzed in various mammalian models, few studies have considered NLRs in teleost species. Therefore, this study analyzed the Atlantic salmon (Salmo salar) NLRC5. Structurally, Atlantic salmon NLRC5 presented leucine-rich repeat subfamily genes. Phylogenetically, NLRC5 was moderately conserved between S. salar and other species. Real-time quantitative PCR revealed NLRC5 expression in almost all analyzed organs, with greatest expressions in the head kidney, spleen, and hindgut. Furthermore, NLRC5 gene expression decreased during smolt stage. These data suggest that NLRC5 participates in the Atlantic salmon immune response and is regulated, at least partly, by the smoltification process, suggesting that there is a depression of immune system from parr at smolt stage. This is the first report on the NLRC5 gene in salmonid smolts.

Toll-like receptor 2 and type 2 diabetes.

Innate immunity plays a crucial role in the pathogenesis of type 2 diabetes and related complications. Since the toll-like receptors (TLRs) are central to innate immunity, it appears that they are important participants in the development and pathogenesis of the disease. Previous investigations demonstrated that TLR2 homodimers and TLR2 heterodimers with TLR1 or TLR6 activate innate immunity upon recognition of damage-associated molecular patterns (DAMPs). Several DAMPs are released during type 2 diabetes, so it may be hypothesized that TLR2 is significantly involved in its progression. Here, we review recent data on the important roles and status of TLR2 in type 2 diabetes and related complications.

Cracking the ANP32 whips: important functions, unequal requirement, and hints at disease implications.

The acidic (leucine-rich) nuclear phosphoprotein 32 kDa (ANP32) family is composed of small, evolutionarily conserved proteins characterized by an N-terminal leucine-rich repeat domain and a C-terminal low-complexity acidic region. The mammalian family members (ANP32A, ANP32B, and ANP32E) are ascribed physiologically diverse functions including chromatin modification and remodelling, apoptotic caspase modulation, protein phosphatase inhibition, as well as regulation of intracellular transport. In addition to reviewing the widespread literature on the topic, we present a concept of the ANP32s as having a whip-like structure. We also present hypotheses that ANP32C and other intronless sequences should not currently be considered bona fide family members, that their disparate necessity in development may be due to compensatory mechanisms, that their contrasting roles in cancer are likely context-dependent, along with an underlying hypothesis that ANP32s represent an important node of physiological regulation by virtue of their diverse biochemical activities.