The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation.

Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.

Arabidopsis CALCIUM-DEPENDENT PROTEIN KINASE4/5/6/11 negatively regulate hydrotropism via phosphorylation of MIZU-KUSSEI1.

Hydrotropism facilitates the orientation of plant roots towards regions of elevated water potential, enabling them to absorb adequate water. Although calcium signaling plays a crucial role in plant response to water tracking, the exact regulatory mechanisms remain a mystery. Here, we employed the Arabidopsis (Arabidopsis thaliana) hydrotropism-specific protein MIZU-KUSSEI1 (MIZ1) as bait and found that calcium-dependent protein kinases4/5/6/11 (CPK4/5/6/11) interacted with MIZ1 in vitro and in vivo. The cpk4/5/6/11 mutant exhibited increased sensitivity to water potential and enhanced root tip curvature. Furthermore, CPK4/5/6/11 primarily phosphorylated MIZ1 at Ser14/36 residues. Additionally, CPK-mediated phosphorylation of MIZ1 relieved its inhibitory effect on the activity of the endoplasmic reticulum-localized Ca2+ pump ECA1, altering the balance between cytoplasmic Ca2+ inflow and outflow, thereby negatively regulating the hydrotropic growth of plants. Overall, our findings unveil the molecular mechanisms by which the CPK4/5/6/11-MIZ1 module functions in regulating plant hydrotropism responses and provide a theoretical foundation for enhancing plant water use efficiency and promoting sustainable agriculture.

Low NDRG2, regulated by the MYC/MIZ-1 complex and methylation, predicts poor outcomes in DLBCL patients.

Diffuse large B-cell lymphoma (DLBCL) represents the most common tumor in non-Hodgkin's lymphoma. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor highly expressed in healthy tissues but downregulated in many cancers. Although cell proliferation-related metabolism rewiring has been well characterized, less is known about the mechanism of metabolic changes with DLBCL. Herein, we investigated the expressions of NDRG2, MYC and Myc-interacting zinc finger protein 1 (MIZ-1) in seven human lymphoma (mostly DLBCLs) cell lines. NDRG2 expression was inversely correlated with the expressions of MYC and MIZ-1. Further, we explored the regulatory mechanism and biological functions underlying the lymphomagenesis involving NDRG2, MYC and MIZ-1. MYC and MIZ-1 promoted DLBCL cell proliferation, while NDRG2 induced apoptosis in LY8 cells. Moreover, NDRG2 methylation was reversed by the 5-Aza-2'-deoxycytidine (5-Aza-CDR) treatment, triggering the downregulation of MYC and inhibiting DLBCL cell survival. MYC interacts with NDRG2 to regulate energy metabolism associated with mTOR. Remarkably, supporting the biological significance, the converse correlation between NDRG2 and MYC was observed in human DLBCL tumor tissues (R = -0.557). Bioinformatics analysis further validated the association among NDRG2, MYC, MIZ-1, mTOR, and related metabolism genes. Additionally, NDRG2 (P = 0.001) and MYC (P < 0.001) were identified as promising prognostic biomarkers in DLBCL patients through survival analysis. Together, our data demonstrate that the MYC/MIZ-1 complex interplays with NDRG2 to influence the proliferation and apoptosis of DLBCL cells and show the characterizations of NDRG2, MYC and MIZ-1 for metabolism features and prediction prognosis in DLBCL.

A TNFα/Miz1-positive feedback loop inhibits mitophagy in hepatocytes and propagates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory disease that can further progress to cirrhosis and hepatocellular carcinoma. However, the key molecular mechanisms behind this process have not been clarified. METHODS: We analyzed human NASH and normal liver tissue samples by RNA-sequencing and liquid chromatography-mass spectrometry, identifying hepatocyte cytosolic protein Myc-interacting zinc-finger protein 1 (Miz1) as a potential target in NASH progression. We established a Western diet+fructose-induced NASH model in hepatocyte-specific Miz1 knockout and adeno-associated virus type 8-overexpressing mice. Human NASH liver organoids were used to confirm the mechanism, and immunoprecipitation and mass spectrometry were used to detect proteins that could interact with Miz1. RESULTS: We demonstrate that Miz1 is reduced in hepatocytes in human NASH. Miz1 is shown to bind to peroxiredoxin 6 (PRDX6), retaining it in the cytosol, blocking its interaction with mitochondrial Parkin at Cys431, and inhibiting Parkin-mediated mitophagy. In NASH livers, loss of hepatocyte Miz1 results in PRDX6-mediated inhibition of mitophagy, increased dysfunctional mitochondria in hepatocytes, and production of proinflammatory cytokines, including TNFα, by hepatic macrophages. Crucially, the increased production of TNFα results in a further reduction in hepatocyte Miz1 by E3-ubiquitination. This produces a positive feedback loop of TNFα-mediated hepatocyte Miz1 degradation, resulting in PRDX6-mediated inhibition of hepatocyte mitophagy, with the accumulation of dysfunctional mitochondria in hepatocytes and increased macrophage TNFα production. CONCLUSIONS: Our study identified hepatocyte Miz1 as a suppressor of NASH progression via its role in mitophagy; we also identified a positive feedback loop by which TNFα production induces degradation of cytosolic Miz1, which inhibits mitophagy and thus leads to increased macrophage TNFα production. Interruption of this positive feedback loop could be a strategy to inhibit the progression of NASH. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) is a chronic inflammatory disease that can further develop into cirrhosis and hepatocellular carcinoma. However, the key molecular mechanism of this process has not been fully clarified. Herein, we identified a positive feedback loop of macrophage TNFα-mediated hepatocyte Miz1 degradation, resulting in PRDX6-mediated inhibition of hepatocyte mitophagy, aggravation of mitochondrial damage and increased macrophage TNFα production. Our findings not only provide mechanistic insight into NASH progression but also provide potential therapeutic targets for patients with NASH. Our human NASH liver organoid culture is therefore a useful platform for exploring treatment strategies for NASH development.

MIZ1 acts downstream of PGM1 in regulating root hydrotropism.

The MIZ1 play an important role in root hydrotropism. However, the relationship between MIZ1-regulated hydrotropism and amyloplast-mediated gravitropism remain largely unclear. Here, we generated the miz1/pgm1 double mutants by crossing the non-hydrotropic miz1 mutant with the amyloplast-defective pgm1 mutant, which lacks gravitropic response. Our results showed that the miz1/pgm1 mutants exhibited a significant reduction in amyloplast and gravitropic bending, while maintaining a similar ahydrotropic phenotype as the miz1 single mutant. These findings suggest that MIZ1 plays a role in hydrotropism downstream of PGM1. Understanding the mechanisms of interaction between hydrotropism and gravitropism is crucial for comprehending the rooting patterns of plants in natural conditions. The counteracting relationship between root hydrotropism and gravitropism in the miz1 mutant should receive attention in this field, particularly considering the interference from gravitropism on Earth.

MIZU-KUSSEI1 (MIZ1) and GNOM/MIZ2 control not only positive hydrotropism but also phototropism in Arabidopsis roots.

In response to unilateral blue light illumination, roots of some plant species such as Arabidopsis thaliana exhibit negative phototropism (bending away from light), which is important for light avoidance in nature. MIZU-KUSSEI1 (MIZ1) and GNOM/MIZ2 are essential for positive hydrotropism (i.e. in the presence of a moisture gradient, root bending towards greater water availability). Intriguingly, mutations in these genes also cause a substantial reduction in phototropism. Here, we examined whether the same tissue-specific sites of expression required for MIZ1- and GNOM/MIZ2-regulated hydrotropism in Arabidopsis roots are also required for phototropism. The attenuated phototropic response of miz1 roots was completely restored when a functional MIZ1-green fluorescent protein (GFP) fusion was expressed in the cortex of the root elongation zone but not in other tissues such as root cap, meristem, epidermis, or endodermis. The hydrotropic defect and reduced phototropism of miz2 roots were restored by GNOM/MIZ2 expression in either the epidermis, cortex, or stele, but not in the root cap or endodermis. Thus, the sites in root tissues that are involved in the regulation of MIZ1- and GNOM/MIZ2-dependent hydrotropism also regulate phototropism. These results suggest that MIZ1- and GNOM/MIZ2-mediated pathways are, at least in part, shared by hydrotropic and phototropic responses in Arabidopsis roots.

Suppression of Allergic Asthma by Loss of Function of Miz1-mediated Th1 Skewing.

Asthma is the most prevalent chronic respiratory disease worldwide. There is currently no cure, and it remains an important cause of morbidity and mortality. Here we report that lung-specific loss of function of the transcription factor Miz1 (c-Myc-interacting zinc finger protein-1) upregulates the pro-T-helper cell type 1 cytokine IL-12. Upregulation of IL-12 in turn stimulates a Th1 response, thereby counteracting T-helper cell type 2 response and preventing the allergic response in mouse models of house dust mite- and OVA (ovalbumin)-induced asthma. Using transgenic mice expressing Cre under a cell-specific promoter, we demonstrate that Miz1 acts in lung epithelial cells and dendritic cells in asthma. Chromatin immunoprecipitation coupled with high-throughput DNA sequencing or quantitative PCR reveals the binding of Miz1 on the Il12 promoter indicating direct repression of IL-12 by Miz1. In addition, HDAC1 (histone deacetylase 1) is recruited to the Il12 promoter in a Miz1-depdenent manner, suggesting epigenetic repression of Il12 by Miz1. Furthermore, Miz1 is upregulated in the lungs of asthmatic mice. Our data together suggest that Miz1 is upregulated during asthma, which in turn promotes asthma pathogenesis by preventing Th1 skewing through the transcriptional repression of IL-12.

MIZ1 regulates ECA1 to generate a slow, long-distance phloem-transmitted Ca2+ signal essential for root water tracking in Arabidopsis.

Ever since Darwin postulated that the tip of the root is sensitive to moisture differences and that it "transmits an influence to the upper adjoining part, which bends towards the source of moisture" [Darwin C, Darwin F (1880) The Power of Movement in Plants, pp 572-574], the signal underlying this tropic response has remained elusive. Using the FRET-based Cameleon Ca2+ sensor in planta, we show that a water potential gradient applied across the root tip generates a slow, long-distance asymmetric cytosolic Ca2+ signal in the phloem, which peaks at the elongation zone, where it is dispersed laterally and asymmetrically to peripheral cells, where cell elongation occurs. In addition, the MIZ1 protein, whose biochemical function is unknown but is required for root curvature toward water, is indispensable for generating the slow, long-distance Ca2+ signal. Furthermore, biochemical and genetic manipulations that elevate cytosolic Ca2+ levels, including mutants of the endoplasmic reticulum (ER) Ca2+-ATPase isoform ECA1, enhance root curvature toward water. Finally, coimmunoprecipitation of plant proteins and functional complementation assays in yeast cells revealed that MIZ1 directly binds to ECA1 and inhibits its activity. We suggest that the inhibition of ECA1 by MIZ1 changes the balance between cytosolic Ca2+ influx and efflux and generates the cytosolic Ca2+ signal required for water tracking.

Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15.

Tumorigenesis results from dysregulation of oncogenes and tumor suppressors that influence cellular proliferation, differentiation, apoptosis, and/or senescence. Many gene products involved in these processes are substrates of the E3 ubiquitin ligase Mule/Huwe1/Arf-BP1 (Mule), but whether Mule acts as an oncogene or tumor suppressor in vivo remains controversial. We generated K14Cre;Mule(flox/flox(y)) (Mule kKO) mice and subjected them to DMBA/PMA-induced skin carcinogenesis, which depends on oncogenic Ras signaling. Mule deficiency resulted in increased penetrance, number, and severity of skin tumors, which could be reversed by concomitant genetic knockout of c-Myc but not by knockout of p53 or p19Arf. Notably, in the absence of Mule, c-Myc/Miz1 transcriptional complexes accumulated, and levels of p21CDKN1A (p21) and p15INK4B (p15) were down-regulated. In vitro, Mule-deficient primary keratinocytes exhibited increased proliferation that could be reversed by Miz1 knockdown. Transfer of Mule-deficient transformed cells to nude mice resulted in enhanced tumor growth that again could be abrogated by Miz1 knockdown. Our data demonstrate in vivo that Mule suppresses Ras-mediated tumorigenesis by preventing an accumulation of c-Myc/Miz1 complexes that mediates p21 and p15 down-regulation.

Comparative analysis reveals gravity is involved in the MIZ1-regulated root hydrotropism.

Hydrotropism is the directed growth of roots toward the water found in the soil. However, mechanisms governing interactions between hydrotropism and gravitropism remain largely unclear. In this study, we found that an air system and an agar-sorbitol system induced only oblique water-potential gradients; an agar-glycerol system induced only vertical water-potential gradients; and a sand system established both oblique and vertical water-potential gradients. We employed obliquely oriented and vertically oriented experimental systems to study hydrotropism in Arabidopsis and tomato plants. Comparative analyses using different hydrotropic systems showed that gravity hindered the ability of roots to search for obliquely oriented water, whilst facilitating roots' search for vertically oriented water. We found that the gravitropism-deficient mutant aux1 showed enhanced hydrotropism in the oblique orientation but impaired root elongation towards water in the vertical orientation. The miz1 mutant exhibited deficient hydrotropism in the oblique orientation but normal root elongation towards water in the vertical orientation. Importantly, in contrast to miz1, the miz1/aux1 double mutant exhibited hydrotropic bending in the oblique orientation and attenuated root elongation towards water in the vertical orientation. Our results suggest that gravitropism is required for MIZ1-regulated root hydrotropism in both the oblique orientation and the vertical orientation, providing further insight into the role of gravity in root hydrotropism.

Molecular mechanisms mediating root hydrotropism: what we have observed since the rediscovery of hydrotropism.

Roots display directional growth toward moisture in response to a water potential gradient. Root hydrotropism is thought to facilitate plant adaptation to continuously changing water availability. Hydrotropism has not been as extensively studied as gravitropism. However, comparisons of hydrotropic and gravitropic responses identified mechanisms that are unique to hydrotropism. Regulatory mechanisms underlying the hydrotropic response appear to differ among different species. We recently performed molecular and genetic analyses of root hydrotropism in Arabidopsis thaliana. In this review, we summarize the current knowledge of specific mechanisms mediating root hydrotropism in several plant species.

Miz1 Controls Schwann Cell Proliferation via H3K36me2 Demethylase Kdm8 to Prevent Peripheral Nerve Demyelination.

Schwann cell differentiation and myelination depends on chromatin remodeling, histone acetylation, and methylation, which all affect Schwann cell proliferation. We previously reported that the deletion of the POZ (POxvirus and Zinc finger) domain of the transcription factor Miz1 (Myc-interacting zinc finger protein; encoded by Zbtb17) in mouse Schwann cells (Miz1ΔPOZ) causes a neuropathy at 90 d after birth [postnatal day (P) 90], with a subsequent spontaneous regeneration. Here we show that RNA sequencing from Miz1ΔPOZ and control animals at P30 revealed a set of upregulated genes with a strong correlation to cell-cycle regulation. Consistently, a subset of Schwann cells did not exit the cell cycle as observed in control animals and the growth fraction increased over time. From the RNAseq gene list, two direct Miz1 target genes were identified, one of which encodes the histone H3K36me2 demethylase Kdm8. We show that the expression of Kdm8 is repressed by Miz1 and that its release in Miz1ΔPOZ cells induces a decrease of H3K36me2, especially in deregulated cell-cycle-related genes. The linkage between elevated Kdm8 expression, hypomethylation of H3K36 at cell-cycle-relevant genes, and the subsequent re-entering of adult Schwann cells into the cell cycle suggests that the release of Kdm8 repression in the absence of a functional Miz1 is a central issue in the development of the Miz1ΔPOZ phenotype.SIGNIFICANCE STATEMENT The deletion of the Miz1 (Myc-interacting zinc finger protein 1) POZ (POxvirus and Zinc finger) domain in Schwann cells causes a neuropathy. Here we report sustained Schwann cell proliferation caused by an increased expression of the direct Miz1 target gene Kdm8, encoding a H3K36me2 demethylase. Hence, the demethylation of H3K36 is linked to the pathogenesis of a neuropathy.

Repression of SRF target genes is critical for Myc-dependent apoptosis of epithelial cells.

Oncogenic levels of Myc expression sensitize cells to multiple apoptotic stimuli, and this protects long-lived organisms from cancer development. How cells discriminate physiological from supraphysiological levels of Myc is largely unknown. Here, we show that induction of apoptosis by Myc in breast epithelial cells requires association of Myc with Miz1. Gene expression and ChIP-Sequencing experiments show that high levels of Myc invade target sites that lack consensus E-boxes in a complex with Miz1 and repress transcription. Myc/Miz1-repressed genes encode proteins involved in cell adhesion and migration and include several integrins. Promoters of repressed genes are enriched for binding sites of the serum-response factor (SRF). Restoring SRF activity antagonizes Myc repression of SRF target genes, attenuates Myc-induced apoptosis, and reverts a Myc-dependent decrease in Akt phosphorylation and activity, a well-characterized suppressor of Myc-induced apoptosis. We propose that high levels of Myc engage Miz1 in repressive DNA binding complexes and suppress an SRF-dependent transcriptional program that supports survival of epithelial cells.

Miz-1 and Max compete to engage c-Myc: implication for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1.

c-Myc is a basic helix-loop-helix leucine zipper (b-HLH-LZ) transcription factor deregulated in the majority of human cancers. As a heterodimer with Max, another b-HLH-LZ transcription factor, deregulated and persistent c-Myc accumulates at transcriptionally active promoters and enhancers and amplifies transcription. This leads to the so-called transcriptional addiction of tumor cells. Recent studies have showed that c-Myc transcriptional activities can be reversed by its association with Miz-1, a POZ transcription factor containing 13 classical zinc fingers. Although evidences have led to suggest that c-Myc interacts with both Miz-1 and Max to form a ternary repressive complex, earlier evidences also suggest that Miz-1 and Max may compete to engage c-Myc. In such a scenario, the Miz-1/c-Myc complex would be the entity responsible for the inhibition of c-Myc transcriptional amplification. Considering the implications of the Miz-1/c-Myc interaction, it is highly important to solve this duality. While two potential c-Myc interacting domains (hereafter termed MID) have been identified in Miz-1 by yeast two-hybrid, with the b-HLH-LZ as a bait, the biophysical characterization of these interactions has not been reported so far. Here, we report that the MID located between the 12th and 13th zinc finger of Miz-1 and the b-HLH-LZ of Max compete to form a complex with the b-HLH-LZ of c-Myc. Our results support the notion that the repressive action of Miz-1 on c-Myc does not rely on the formation of a ternary complex. The implications of these observations for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1 are discussed. Proteins 2017; 85:199-206. © 2016 Wiley Periodicals, Inc.

Miz-1 regulates translation of Trp53 via ribosomal protein L22 in cells undergoing V(D)J recombination.

To be effective, the adaptive immune response requires a large repertoire of antigen receptors, which are generated through V(D)J recombination in lymphoid precursors. These precursors must be protected from DNA damage-induced cell death, however, because V(D)J recombination generates double-strand breaks and may activate p53. Here we show that the BTB/POZ domain protein Miz-1 restricts p53-dependent induction of apoptosis in both pro-B and DN3a pre-T cells that actively rearrange antigen receptor genes. Miz-1 exerts this function by directly activating the gene for ribosomal protein L22 (Rpl22), which binds to p53 mRNA and negatively regulates its translation. This mechanism limits p53 expression levels and thus contains its apoptosis-inducing functions in lymphocytes, precisely at differentiation stages in which V(D)J recombination occurs.

Late onset neuropathy with spontaneous clinical remission in mice lacking the POZ domain of the transcription factor Myc-interacting zinc finger protein 1 (Miz1) in Schwann cells.

The transcription factor Miz1 (Myc-interacting zinc finger 1) is a known regulator of the cell cycle but also has cell cycle-independent functions. Here we analyzed the role of Miz1 in the peripheral nervous system, using an early embryonic conditional knock-out model in which the Miz1 POZ domain is ablated in Schwann cells. Although the development of myelinated nerve fibers was not impaired, Miz1ΔPOZ mice acquired behavioral signs of a peripheral neuropathy at the age of 3 months. At this time, ultrastructural analysis of the sciatic nerve showed de- and dysmyelination of fibers, with massive outfoldings and a focal infiltration of macrophages. Although the expression of genes encoding structural myelin proteins, such as periaxin, myelin basic protein, and myelin protein zero, was decreased, genes associated with a negative regulation of myelination, including c-Jun, Sox2, and Id2, were up-regulated in Miz1ΔPOZ mice compared with controls. In animals older than 4 months, the motor disabilities vanished, and the ultrastructure of the sciatic nerve exhibited numerous tomacula and remyelinated fibers, as indicated by thinner myelin. No second acute attack was observed up to the age of 1 year. Thus, the deletion of the Miz1 POZ domain in Schwann cells induces an acute neuropathy with a subsequent regeneration in which there is ongoing balancing between de- and remyelination. Miz1ΔPOZ mice are impaired in the maintenance of myelinated fibers and are a promising model for studying remyelination in adult peripheral nerves.

Decreased MIZ1 Expression in Severe Experimental Acute Pancreatitis: A Rat Study.

AIM: We tested our hypothesis that Myc-interacting zinc finger protein 1 (MIZ1), a cell cycle regulator, suppressed inflammation, and therefore, represented a useful prognostic marker in patients with acute necrotizing pancreatitis (ANP) complicated by acute lung injury. METHODS: Sprague-Dawley rats were randomly divided into control and ANP groups at different time points. The MIZ1 protein expression was measured by Western blot and ELISA, and confirmed using immunohistochemistry. The severity of pancreatic and lung injury was evaluated by the injury score and wet/dry weight ratio. The severity of disease was evaluated by serum C-reactive protein (CRP). The MPO activity of lung tissue amylase levels and the degree of inflammation were evaluated by serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 expression. The risk due to multiple factors was investigated by relationship analysis. RESULTS: The serum levels of CRP, amylase, TNF-α, and IL-6 were gradually increased at 6, 24, and 48 h in ANP when compared with the control rats. The MIZ1 expressions were greatly decreased in ANP rats, especially at 24 h. Statistical analysis showed that there were time-dependent differences in ANP rats when compared with control rats (6 vs. 24 or 48 h, P < 0.01). MIZ1 showed close negative correlation with the degree of pancreatic and lung injury, serum amylase, CRP, TNF-α, and IL-6 (P < 0.01, respectively). CONCLUSION: The decreasing MIZ1 expression was closely correlated with inflammatory response, and development of ANP. Decreasing MIZ1 levels indicate a risk for ANP.

Amyloplast is involved in the MIZ1-modulated root hydrotropism.

Roots exhibit hydrotropism in response to moisture gradients, with the hydrotropism-related gene Mizu-kussei1 (MIZ1) playing a role in regulating root hydrotropism in an oblique orientation. However, the mechanisms underlying MIZ1-regulated root hydrotropism are not well understood. In this study, we employed obliquely oriented experimental systems to investigate root hydrotropism in Arabidopsis. We found that the miz1 mutant displays reduced root hydrotropism but increased root gravitropism following hydrostimulation, as compared to wild-type plants. Conversely, overexpression of AtMIZ1 leads to enhanced root hydrotropism but decreased root gravitropism following hydrostimulation, as compared to wild-type plants. Using co-immunoprecipitation followed by mass spectrometry (IP-MS), we explored proteins that interact with AtMIZ1, and we identified PGMC1 co-immunoprecipitated with MIZ1 in vivo. Furthermore, the miz1 mutant exhibited higher expression of the PGMC1 gene and increased phosphoglucomutase (PGM) activity, while AtMIZ1 overexpressors resulted in lower expression of the PGMC1 gene, reduced amyloplast amount, and reduced PGM activity in comparison to wild-type roots. In addition, different Arabidopsis natural accessions having difference in their hydrotropic response demonstrated expression level of PGMC1 was negatively correlated with hydrotropic root curvature and AtMIZ1 expression. Our results provide valuable insights into the role of amyloplast in MIZ1-regulated root hydrotropism.

Recovery of root hydrotropism in miz1 mutant by eliminating root gravitropism.

Mizu-kussei1 (MIZ1) plays a crucial role in root hydrotropism, but it is still unclear whether auxin-mediated gravitropism is involved in MIZ1-modulated root hydrotropism. This study aimed to investigate whether the hydrotropism of the Arabidopsis miz1 mutants could be restored through pharmacological inhibition of auxin transport or genetic modification in root gravitropism. Our findings indicate that the hydrotropic defects of miz1 mutant can be partly recovered by using an auxin transport inhibitor. Furthermore, miz1/pin2 double mutants exhibit more pronounced defects in root gravitropism compared to the wild type, while still displaying a normal hydrotropic response similar to the wild type. These results suggest that the elimination of gravitropism enables miz1 roots to become hydrotropically responsive to moisture gradients.

Unraveling Novel Strategies: Targeting Miz1 for Degradation to Enhance Antiviral Defense against Influenza A Virus.

The ubiquitin system has been shown to play an important role in regulation of immune responses during viral infection. In a recent article published in Science Signaling, Wu and colleagues revealed that transcriptional factor Miz1 plays a pro-viral role in influenza A virus (IAV) infection by suppressing type I interferons (IFNs) production through recruiting HDAC1 to ifnb1 promoter. They show that a series of E3 ligases combinatorially regulates Miz1 ubiquitination and degradation and modulates IFNs production and viral replication.