TIAF1 Human

What is the molecular identity of TIAF1 and its basic genetic properties?

TIAF1 (TGFB1-induced anti-apoptotic factor 1) is a protein encoded by the TIAF1 gene in humans. It is also known by several aliases including MAJN and SPR210, with an NCBI Gene ID of 9220 . This protein was initially identified as a TGF-β1-induced factor with anti-apoptotic properties. The human TIAF1 protein is characterized by its relatively small size, functioning as a regulatory protein in multiple cellular pathways .

TIAF1 has demonstrated significant evolutionary conservation, with homologs identified in multiple species including bovine forms (cow TIAF1, gene ID: 101903486) . This conservation suggests fundamental biological importance across mammalian species. The protein's molecular structure contains domains that facilitate its interactions with multiple binding partners, contributing to its diverse functional capabilities.

What protein interactions has TIAF1 been confirmed to participate in?

TIAF1 engages in several critical protein-protein interactions that define its functional roles. Confirmed interaction partners include:

These interaction networks position TIAF1 at the intersection of multiple critical cellular processes. When investigating these interactions experimentally, co-immunoprecipitation with specific antibodies like SAB1412775 (monoclonal anti-TIAF1) or HPA051129 (polyclonal anti-TIAF1) can be employed for protein complex isolation and analysis .

How is TIAF1 expression regulated across different tissues and pathological states?

TIAF1 demonstrates tissue-specific expression patterns that are further altered in pathological conditions. Based on analysis of expression databases and clinical studies:

• TIAF1 shows differential expression in neural tissues, with specific patterns during brain development according to Allen Brain Atlas data .

• The protein is significantly upregulated in activated helper T lymphocytes (TH2) during chronic kidney and liver allograft rejection, suggesting immunological functions .

• Expression analysis across multiple datasets indicates that TIAF1 has at least 1,297 functional associations with biological entities spanning 7 categories, extracted from 44 datasets .

For experimental determination of TIAF1 expression:

• RNA-seq or qRT-PCR can quantify transcript levels using gene-specific primers

• Immunohistochemistry with antibodies like HPA051129 allows visualization in tissue sections

• Western blot analysis provides quantitative protein expression data across sample types

What is the functional relationship between TIAF1 and the TGF-β signaling pathway?

TIAF1 exhibits a complex relationship with TGF-β signaling through multiple mechanisms:

• TIAF1 physically interacts with Smad4, a central mediator of canonical TGF-β signaling, blocking SMAD-dependent promoter activation when overexpressed .

• Knockdown experiments using siRNA against TIAF1 result in spontaneous accumulation of Smad proteins in the nucleus and activation of SMAD-governed promoters, confirming its inhibitory role in this pathway .

• Most notably, TGF-β1 can induce TIAF1 self-aggregation through a non-canonical mechanism that operates independently of the type II TGF-β receptor, representing an alternative signaling pathway .

• Smad4 has been demonstrated to interrupt TIAF1 self-aggregation, establishing a regulatory feedback mechanism within this signaling axis .

For researchers investigating this pathway, experimental approaches should include:

• Luciferase reporter assays with SMAD binding elements to assess transcriptional effects

• Subcellular fractionation to monitor Smad nuclear translocation

• Protein aggregation assays to detect TIAF1 self-assembly following TGF-β1 stimulation

• Co-expression studies of TIAF1 and Smad4 to examine their functional interdependence

How does TIAF1 participate in cell death regulation and apoptotic pathways?

TIAF1 demonstrates contextual duality in apoptotic regulation, functioning as:

• An anti-apoptotic factor that inhibits the cytotoxic effects of TNF-alpha, TRADD, and FADD under normal conditions, protecting cells from death receptor-mediated apoptosis .

• Paradoxically, when TIAF1 undergoes self-aggregation, it converts to a pro-apoptotic factor, inducing cell death through caspase-dependent mechanisms .

• A critical component in p53- and WOX1-mediated apoptotic pathways, with suppression of TIAF1 by siRNA preventing UV irradiation-mediated p53 phosphorylation and nuclear translocation .

To investigate these dual roles, researchers should consider:

• Time-course analyses following apoptotic stimuli with measurement of TIAF1 aggregation status

• Caspase activity assays in contexts of TIAF1 overexpression, knockdown, and aggregation

• Co-localization studies with death receptor components and p53 pathway elements

• Mutational analyses to identify domains responsible for anti- versus pro-apoptotic functions

What signaling crosstalk exists between TIAF1 and inflammatory pathways?

While direct evidence for TIAF1 in inflammatory signaling is limited in the provided search results, several connections can be inferred:

• TIAF1 interactions with JAK3 suggest potential involvement in cytokine signaling cascades that regulate inflammatory responses .

• The upregulation of TIAF1 in TH2 lymphocytes during allograft rejection points to roles in adaptive immunity and potential inflammatory regulation .

• Though a genetic association study did not demonstrate strong evidence for TIAF1 involvement in Crohn's disease susceptibility, this does not exclude functional roles in inflammatory conditions .

Given these connections, researchers investigating inflammatory aspects should:

• Examine TIAF1 expression and aggregation status in inflammatory cell populations

• Assess cytokine production profiles in TIAF1-manipulated systems

• Investigate potential post-translational modifications of TIAF1 during inflammatory activation

• Consider TIAF1's relationship with NF-κB and other inflammatory transcription factors

What evidence links TIAF1 to Alzheimer's disease development?

TIAF1 has emerged as a significant factor in Alzheimer's disease (AD) pathogenesis through several mechanisms:

• TIAF1 aggregates have been identified in hippocampal tissues of both non-demented individuals and AD patients, with significantly higher prevalence in AD cases (48% versus 17% in non-demented controls), suggesting TIAF1 aggregation may precede amyloid β (Aβ) plaque formation .

• Mechanistic studies reveal that TGF-β-regulated TIAF1 aggregation initiates a cascade of events leading to:

  • Dephosphorylation of amyloid precursor protein (APP) at Thr668

  • Subsequent APP degradation

  • Generation of APP intracellular domain (AICD)

  • Production of Aβ peptides and amyloid fibrils

• Polymerized TIAF1 physically interacts with amyloid fibrils, potentially stabilizing and promoting plaque formation in vivo .

This temporal relationship is visualized in the following progression model:

These findings position TIAF1 as a potential upstream mediator in AD pathogenesis, worthy of consideration as both a biomarker and therapeutic target.

What experimental methodologies are most effective for studying TIAF1 in neurodegenerative contexts?

When investigating TIAF1 in neurodegenerative diseases, researchers should employ multiple complementary approaches:

• For detection of TIAF1 aggregates in neural tissues:

  • Filter retardation assay (the method used to identify aggregates in hippocampal samples)

  • Immunohistochemistry with specific antibodies like HPA051129

  • Conformation-specific antibodies to distinguish native versus aggregated forms

• For examining TIAF1-amyloid interactions:

  • Co-immunoprecipitation of TIAF1 with Aβ species

  • Proximity ligation assays in tissue sections or cell models

  • In vitro binding studies with purified components

  • Electron microscopy to visualize physical interactions

• For modeling TIAF1 pathogenic mechanisms:

  • Transgenic animal models with TIAF1 overexpression or conditional knockout

  • Neural cell cultures with manipulated TIAF1 expression

  • Patient-derived iPSCs differentiated into relevant neural cell types

  • Organoid models to capture complex cellular interactions

• For therapeutic targeting:

  • Small molecule screening against TIAF1 aggregation

  • Peptide inhibitors of TIAF1-amyloid interactions

  • Antisense oligonucleotides to modulate TIAF1 expression

When designing these experiments, researchers should account for the temporal aspects of TIAF1 involvement, potentially focusing on early-stage processes before overt amyloid pathology.

What is known about TIAF1's potential involvement in cancer progression?

TIAF1 demonstrates complex roles in cancer biology through multiple mechanisms:

• TIAF1 shows aggregation-dependent control of tumor progression and metastasis, with its aggregation state potentially serving as a molecular switch .

• The protein plays essential roles in p53- and WOX1-mediated cell death pathways, which are frequently dysregulated in cancer .

• The duality of TIAF1 as both an anti-apoptotic factor under normal conditions and a potential pro-apoptotic factor when aggregated suggests context-dependent functions in tumorigenesis .

These observations raise several research questions for oncology investigations:

• Does TIAF1 aggregation status correlate with cancer stage or prognosis?

• How do cancer cells manipulate TIAF1 to evade apoptosis?

• Are there cancer-specific mutations or modifications of TIAF1?

• Could targeting TIAF1 aggregation represent a therapeutic strategy?

Methodologically, researchers should consider:

• Comprehensive profiling of TIAF1 expression and aggregation across cancer types

• Analysis of TIAF1 in paired normal-tumor samples to identify alterations

• Correlation of TIAF1 status with p53 pathway functionality

• Functional studies in cancer cell lines and animal models

What are the optimal methods for manipulating TIAF1 expression in experimental systems?

Several approaches have been validated for modulating TIAF1 expression in research contexts:

When designing knockdown experiments, researchers should:

• Include appropriate non-targeting controls

• Validate knockdown efficiency at both mRNA (qRT-PCR) and protein (Western blot) levels

• Monitor cellular phenotypes, particularly in relation to TGF-β signaling and apoptosis

• Consider potential compensatory mechanisms in long-term studies

Commercial reagents mentioned in the search results include MISSION esiRNA targeting human TIAF1 (EHU221441) , which can provide efficient knockdown for experimental applications.

What challenges exist in detecting and quantifying TIAF1 protein in complex biological samples?

TIAF1 detection presents several technical challenges that researchers should address:

• The protein's potential for self-aggregation can affect antibody accessibility and epitope recognition, necessitating specialized extraction methods.

• TIAF1's relatively small size and potential post-translational modifications require careful selection of detection reagents and conditions.

• The distinction between monomeric, oligomeric, and aggregated forms requires specific methodological approaches.

To overcome these challenges:

• For Western blotting: Consider both reducing and non-reducing conditions to capture different forms

• For immunohistochemistry: Optimize antigen retrieval methods for aggregated proteins

• For aggregation detection: Employ filter retardation assays as used in hippocampal studies

• For quantification: Consider ELISA approaches with capture and detection antibody pairs

Commercial antibodies validated for TIAF1 detection include:

• SAB1412775: Monoclonal Anti-TIAF1 antibody (mouse), validated for ELISA and Western blot

• HPA051129: Polyclonal Anti-TIAF1 antibody (rabbit), validated for immunohistochemistry

• These can be paired with PEP-1581, a synthetic peptide corresponding to 16 amino acids near the amino terminus of human TIAF1, as a blocking peptide for specificity controls

What experimental approaches best capture the functional duality of TIAF1 in cellular systems?

To investigate TIAF1's context-dependent functions (anti-apoptotic versus pro-apoptotic):

• Time-course experiments following specific stimuli:

  • Track TIAF1 aggregation status using biochemical separation

  • Monitor corresponding cellular phenotypes (survival versus death)

  • Assess activation of downstream pathways

• Structure-function analyses:

  • Generate domain-specific mutants to dissect regions responsible for each function

  • Create aggregation-prone versus aggregation-resistant variants

  • Perform rescue experiments in TIAF1-depleted systems

• Single-cell approaches:

  • Utilize live-cell imaging with fluorescently-tagged TIAF1

  • Correlate TIAF1 aggregation status with cellular outcomes

  • Implement single-cell transcriptomics to identify divergent pathway activation

• Stress-response studies:

  • Expose cells to varied stressors (UV, oxidative stress, TGF-β)

  • Monitor TIAF1 conformational changes and interactome dynamics

  • Correlate with downstream pathway activation (apoptotic versus survival)

These approaches should be combined with careful controls and quantitative metrics to capture the transitional states of TIAF1 function.

How might the type II TGF-β receptor-independent aggregation of TIAF1 be mechanistically explained?

The observation that TGF-β1 can induce TIAF1 self-aggregation independent of the canonical type II TGF-β receptor presents a significant mechanistic puzzle . Several hypothetical pathways warrant investigation:

• Direct TGF-β1-TIAF1 interaction:

  • Is there direct binding between TGF-β1 and TIAF1?

  • Could this represent an alternative signaling mechanism?

  • What structural domains mediate this potential interaction?

• Alternative receptor utilization:

  • Does TGF-β1 signal through non-canonical receptors to influence TIAF1?

  • Are there co-receptors or adaptor proteins facilitating this process?

  • How does this pathway intersect with canonical TGF-β signaling?

• Cellular stress as an intermediary:

  • Does TGF-β1 induce cellular stress that subsequently promotes TIAF1 aggregation?

  • What stress response pathways might converge on TIAF1?

  • How do environmental alterations influence this process?

Experimental approaches to address these questions include:

• In vitro reconstitution with purified components to test direct interactions

• Receptor knockout systems to verify independence from canonical pathway

• Proteomic analysis of TIAF1 complexes formed under TGF-β1 stimulation

• Structural studies of TIAF1 conformational changes following various stimuli

What is the precise temporal relationship between TIAF1 aggregation and amyloidogenic processes in neurodegeneration?

The discovery that TIAF1 aggregates appear in both non-demented and AD hippocampi, with higher prevalence in AD, suggests a potential temporal progression . Several critical questions emerge:

• Does TIAF1 aggregation truly precede Aβ deposition in vivo, and by what time frame?

• What triggers the transition from benign to pathogenic TIAF1 aggregation?

• How does aggregated TIAF1 mechanistically lead to APP dephosphorylation?

• What phosphatases are recruited or activated in this process?

To address these questions, researchers should consider:

• Longitudinal studies in animal models with temporal mapping of TIAF1 and Aβ pathology

• Analysis of preclinical AD biomarkers in relation to TIAF1 aggregation status

• Proteomic identification of TIAF1 aggregate-associated phosphatases

• Phosphorylation site-specific mutants of APP to confirm the critical sites

The finding that TIAF1-positive samples containing Aβ aggregates comprise 17% of non-demented versus 48% of AD hippocampi suggests TIAF1 aggregation as a potential early biomarker worthy of further investigation as both a diagnostic tool and therapeutic target .

How can high-throughput screening approaches be optimized to identify modulators of TIAF1 aggregation?

Given TIAF1's potential as a therapeutic target, developing screening platforms for TIAF1 aggregation modulators represents an important research direction:

• Assay development considerations:

  • Recombinant TIAF1 production and purification systems

  • Fluorescence-based aggregation detection methods (ThT/ThS binding)

  • Cell-based reporters of TIAF1 aggregation status

  • Methods to distinguish between beneficial and pathological modulation

• Compound library selection:

  • Known modulators of protein aggregation

  • Natural products with neuroprotective properties

  • Repurposing candidates from other aggregation-related diseases

  • Fragment-based approaches for novel chemical matter

• Validation pipeline design:

  • Secondary assays for mechanism confirmation

  • Cellular models of TIAF1-mediated pathology

  • Selectivity assessments against other aggregation-prone proteins

  • Early ADME and blood-brain barrier penetration studies

• Advanced screening technologies:

  • Surface plasmon resonance for direct binding studies

  • Nuclear magnetic resonance for structural insights

  • High-content imaging for cellular phenotypes

  • Label-free aggregation detection methods

By establishing robust screening platforms, researchers can accelerate the discovery of chemical probes and potential therapeutic candidates targeting TIAF1's role in neurodegenerative and potentially other diseases.