Cellular senescence is a diverse phenotype characterised by permanent cell cycle arrest and an associated secretory phenotype (SASP) which includes inflammatory cytokines. Typically, senescent cells are removed by the immune system, but this process becomes dysregulated with age causing senescent cells to accumulate and induce chronic inflammatory signalling. Identifying senescent cells is challenging due to senescence phenotype heterogeneity, and senotherapy often requires a combinatorial approach. Here we systematically collected 119 transcriptomic datasets related to human fibroblasts, forming an online database describing the relevant variables for each study allowing users to filter for variables and genes of interest. Our own analysis of the database identified 28 genes significantly up- or downregulated across four senescence types (DNA damage induced senescence (DDIS), oncogene induced senescence (OIS), replicative senescence, and bystander induced senescence) compared to proliferating controls. We also found gene expression patterns of conventional senescence markers were highly specific and reliable for different senescence inducers, cell lines, and timepoints. Our comprehensive data supported several observations made in existing studies using single datasets, including stronger p53 signalling in DDIS compared to OIS. However, contrary to some early observations, both p16 and p21 mRNA levels rise quickly, depending on senescence type, and persist for at least 8–11 days. Additionally, little evidence was found to support an initial TGFβ-centric SASP. To support our transcriptomic analysis, we computationally modelled temporal protein changes of select core senescence proteins during DDIS and OIS, as well as perform knockdown interventions. We conclude that while universal biomarkers of senescence are difficult to identify, conventional senescence markers follow predictable profiles and construction of a framework for studying senescence could lead to more reproducible data and understanding of senescence heterogeneity. 

Systematic transcriptomic analysis and temporal modelling of human fibroblast senescence

Cell senescence is a diverse phenotype and therapies often require combinatorial approaches. Here we have systematically collected transcriptomic data related to human fibroblasts to a total of 98 studies. We formed a database describing the relevant variables for each study which we have hosted online allowing users to filter the studies to select variables and genes of interest. Our own analysis of the database revealed 13 marker genes consistently downregulated in senescent cells compared to proliferating controls; however, we also found gene expression patterns that were highly specific and reliable for different senescence inducers, cell lines, and timepoint after induction, confirming several conclusions of existing studies based on single datasets, including differences in p53 and inflammatory signals between oncogene induced senescence (OIS) and DNA damage induced senescence (DDIS). We saw little evidence of an initial TGF-β-centric SASP, but we did find evidence of a decrease in Notch signalling. Contrary to some early observations, both p16 and p21 mRNA levels appeared to rise quickly, depending on senescence type, and persist for at least 8-11 days. We concluded that while universal biomarkers of senescence are difficult to identify, the conventional senescence markers follow predictable profiles and construction of a framework for studying senescence could lead to more reproducible data.

Systematic Analysis and Model of Fibroblast Senescence Transcriptome

ABSTRACT Calumenin (CALU), a multifunctional E‐F‐hand protein of the CREC family involved in various cellular processes, is ubiquitously expressed in almost all human tissues, although its expression level is tissue‐specific. CALU plays an effective role in calcium (Ca) homeostasis throughout various Ca2 + ‐related processes, and its correlations with various ER‐related functions are evident. Due to its propensity to bind Ca, participation in calcium ion (Ca 2+ )‐dependent activities, major cellular processes, such as the production and maintenance of extracellular matrix, have been attributed to this multifaceted protein. In this regard, CALU's association with various normal calcification processes, as well as pathologic Ca deposits, is apparent. Additionally, its key role as a crossroads among various normal cellular processes and many inflammatory diseases and cancers is also evident. The important correlation of CALU with cancer‐related proteins through its regulatory role in γ‐carboxylation of known cancer‐related vitamin K‐dependent proteins has also been noted. The opposing and pleiotropic functions of the CALU isoforms might play balancing roles in establishing a state of equilibrium in the cell. Given the contradictory functions of CALU isoforms during cancer, the need for a balance between these isoforms, as well as the existence of mechanisms to regulate their ratio in normal cells, is speculated. The relationship between CALU and immune response, tumor‐infiltrating immune cells, and cancer patients' responsiveness to various cancer therapies is also described. In this regard, the involvement of the CALU isoform in response to cancer treatment and various immune pathways is discussed. This comprehensive review addresses the outstanding features and the latest findings on CALU's molecular aspects and diverse functions in various physiological processes and pathological conditions. 

Calumenin, A Calcium‐Binding Modulatory Protein, Effective in Pathological Calcifications and Cancers, With Therapeutic Application Promise

Macroautophagy (hereafter referred to as autophagy) degrades a variety of cellular components. A poorly understood area is autophagic degradation of nuclear substrates, or “nuclear autophagy”. It remains unclear what can be degraded by autophagy from the mammalian nuclei. We began our study by investigating the nuclear binding partners of ATG8 family proteins that play important roles in recognizing autophagy substrates. We systematically evaluated the ATG8 nuclear interactome in primary human cells and in mouse brain, identifying hundreds of novel interactions. We continued our study by evaluating the nuclear proteomes of cellular senescence, a stable form of cell cycle arrest program associated with inflammation, in which nuclear autophagy is involved. Combined with the ATG8 nuclear interactome data, we identified WSTF, a component of the ISWI chromatin remodeling complex, as a novel substrate of nuclear autophagy. The degradation of WSTF, mediated by a direct interaction with the GABARAP isoform of ATG8, promotes chromatin accessibility of inflammatory genes and induces senescence-associated inflammation. Furthermore, WSTF directly binds the p65 subunit of NF-κB and inhibits its acetylation, thus blocking inflammatory gene expression in the setting of senescence, cancer, and pathogen infection. In addition, we show that loss of WSTF is required for the immuno-surveillance of oncogenic Ras in mouse liver; forced expression of WSTF inhibited tumor-suppressive inflammation and led to the development of liver tumors. Taken together, our study provides a global view of mammalian nuclear autophagy and reveals a novel nuclear inhibitor of inflammation implicated in diverse pathological contexts. Targeting WSTF may be broadly valuable as therapeutic intervention of inflammatory diseases.

Nuclear autophagy interactome unveils WSTF as a constitutive nuclear inhibitor of inflammation

Autophagy is a catabolic and self-degradative process crucial for maintaining cellular homeostasis. Malfunctional autophagy is implicated in neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we reported a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and LC3-interactome uncovers a role of neuronal autophagy in targeting primarily endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) proteins, and cAMP-PKA pathway, for degradation. Tubular ER and specific SV proteins are significant autophagy cargos in the axons. Functional validation identified calumenin as an ER resident autophagy receptor and illuminated a role of autophagy in regulating PKA and neuronal activity through AKAP11-mediated degradation. Our study thus reveals the landscape of autophagy degradation in human neurons and offers molecular insight into mechanisms of neurological disorders linked to autophagy deficiency. Highlight Integrated proteomics reveals the landscape of autophagy degradation in human neurons Autophagy clears tubular ER and selective ER and synaptic vesicle proteins in neurons Calumenin is an ER resident autophagy receptor Autophagy controls PKA pathway and neuronal activity through autophagy receptor AKAP11

Integrated proteomics reveals the landscape of autophagy degradation in human neurons and autophagy receptors regulating neuronal activity

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Nuclear autophagy interactome unveils WSTF as a constitutive nuclear inhibitor of inflammation

Integrated proteomics reveals the landscape of autophagy degradation in human neurons and autophagy receptors regulating neuronal activity