All Human Granzymes Target hnRNP K That Is Essential for Tumor Cell Viability

Domselaar, Robert van; Quadir, Razi; Made, Astrid M. van der; Broekhuizen, Roel; Bovenschen, Niels

doi:10.1074/jbc.m112.365692

Cited by 28 publications

(30 citation statements)

References 45 publications

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“…hn-RNP K is a substrate for granzyme A (GzmA) and caspases and is cleaved during cell death, and its inactivation is a common attribute during apoptosis (32). hnRNP K suppresses apoptosis by suppressing effector caspase-3 and -7 activities by activating caspase inhibitors (33).…”

Section: Resultsmentioning

confidence: 99%

Proteomic-Based Approach To Gain Insight into Reprogramming of THP-1 Cells Exposed to Leishmania donovani over an Early Temporal Window

et al. 2015

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Leishmania has developed an intricate relationship with its host, primarily cells of the monocyte/macrophage lineage, where it exploits and subverts the host immune system by either inducing immunosuppression or promoting proparasitic host factors to ensure its survival and growth in an otherwise harsh milieu (3). Hijacking of innate immune functions of macrophages by Leishmania appears to be a multifarious event, as macrophages have inherently evolved to defend the host against invading pathogens by a myriad of effectors rather than providing a favorable environment to the pathogen. The chief molecular mechanisms by which Leishmania is known to inhibit the activation of macrophages toward its own benefit include suppression of deadly antimicrobial free radicals such as nitric oxide (NO), faulty antigen presentation, selective induction and suppression of host cell apoptosis, inhibition of cytokine production and hence cytokine-inducible macrophage function, and activation of T cells (4-8). Leishmania has evolved sophisticated mechanisms to alter the physiological program and activation of adaptive immune responses of host cells by exploiting host cell signaling mechanisms such as the downregulation of Ca 2ϩ -dependent classical protein kinase C (PKC) activity and extracellular signal-regulated kinase (ERK) phosphorylation and activity (9, 10). Using mainly host tyrosine phosphatases, Leishmania is known to deactivate mitogen-activated protein kinases (MAPKs) in infected macrophages (5). Extensive manipulations of host cell effector (innate and adaptive) functions by pathogens must be reflected at the levels of transcripts as well as proteins. Enormous efforts made in the field of host gene expression profiling using different (murine and/or human) cell types and different species of Leishmania provide key insights into an extensive modulation of gene function and contribute to a better understanding of the dynamics of gene expres-

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Section: Resultsmentioning

confidence: 99%

Proteomic-Based Approach To Gain Insight into Reprogramming of THP-1 Cells Exposed to Leishmania donovani over an Early Temporal Window

et al. 2015

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“…33 Overexpression of an uncleavable NPM mutant, however, fails to protect tumor cells from hGrMinduced cell death. 33 Similarly, knockdown of heterogeneous nuclear ribonucleoprotein K (hnRNP K) -the first substrate known to be cleaved by all five human granzymes -sensitizes tumor cells to LAK-cell-mediated cytotoxicity, 49 and knockdown of survivin, another hGrM substrate, sensitizes tumor cells to hGrM-induced cell death by lowering the threshold for caspase activation. 44 All of these pathways are likely to contribute to hGrM-induced cell death, but none of these appear to be absolutely essential for apoptosis induction.…”

Section: Functionsmentioning

confidence: 99%

Granzyme M: behind enemy lines

Poot

Bovenschen

2014

Cell Death Differ

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The granule-exocytosis pathway is the major mechanism via which cytotoxic lymphocytes eliminate virus-infected and tumor cells. In this pathway, cytotoxic lymphocytes release granules containing the pore-forming protein perforin and a family of serine proteases known as granzymes into the immunological synapse. Pore-formation by perforin facilitates entry of granzymes into the target cell, where they can activate various (death) pathways. Humans express five different granzymes, of which granzymes A and B have been most extensively characterized. However, much less is known about granzyme M (GrM). Recently, structural analysis and advanced proteomics approaches have determined the primary and extended specificity of GrM. GrM functions have expanded over the past few years: not only can GrM efficiently induce cell death in tumor cells, it can also inhibit cytomegalovirus replication in a noncytotoxic manner. Finally, a role for GrM in lipopolysaccharide-induced inflammatory responses has been proposed. In this review, we recapitulate the current status of GrM expression, substrate specificity, functions, and inhibitors.

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“…hn-RNP K plays essential roles in cell survival. Its cleavage by different granzymes initiates cell death processes, and its depletion primes the cells to undergo programmed cell death under various apoptotic stimuli (9,13,41,42). While performing our studies, we observed that VSV-infected cells depleted of hnRNP K exhibited enhanced cytopathic effects and cell death compared to the infected cells not depleted of the protein.…”

Section: Requirement Of Hnrnp K In Vsv Infectionmentioning

confidence: 61%

“…The observation that hnRNP K is highly expressed in multiple cancerous tissues (9)(10)(11)(12) suggests its possible roles in cancer development and tumorigenesis. On the other hand, its sequestration, deficiency, or degradation marks the initial step for apoptotic progression (13)(14)(15).…”

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confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein K Supports Vesicular Stomatitis Virus Replication by Regulating Cell Survival and Cellular Gene Expression

Dinh

Das

Franco

et al. 2013

J Virol

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The heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a member of the family of hnRNPs and was recently shown in a genome-wide small interfering RNA (siRNA) screen to support vesicular stomatitis virus (VSV) growth. To decipher the role of hnRNP K in VSV infection, we conducted studies which suggest that the protein is required for VSV spreading. Virus binding to cells, entry, and nucleocapsid uncoating steps were not adversely affected in the absence of hnRNP K, whereas viral genome transcription and replication were reduced slightly. These results indicate that hnRNP K is likely involved in virus assembly and/or release from infected cells. Further studies showed that hnRNP K suppresses apoptosis of virus-infected cells, resulting in increased cell survival during VSV infection. The increased survival of the infected cells was found to be due to the suppression of proapoptotic proteins such as Bcl-X S and Bik in a cell-type-dependent manner. Additionally, depletion of hnRNP K resulted in not only significantly increased levels of T-cell-restricted intracellular antigen 1 (TIA1) but also switching of the expression of the two isoforms of the protein (TIA1a and TIA1b), both of which inhibited VSV replication. hnRNP K was also found to support expression of several cellular proteins known to be required for VSV infection. Overall, our studies demonstrate hnRNP K to be a multifunctional protein that supports VSV infection via its role(s) in suppressing apoptosis of infected cells, inhibiting the expression of antiviral proteins, and maintaining the expression of proteins required for the virus.

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All Human Granzymes Target hnRNP K That Is Essential for Tumor Cell Viability

Cited by 28 publications

References 45 publications

Proteomic-Based Approach To Gain Insight into Reprogramming of THP-1 Cells Exposed to Leishmania donovani over an Early Temporal Window

Proteomic-Based Approach To Gain Insight into Reprogramming of THP-1 Cells Exposed to Leishmania donovani over an Early Temporal Window

Granzyme M: behind enemy lines

Heterogeneous Nuclear Ribonucleoprotein K Supports Vesicular Stomatitis Virus Replication by Regulating Cell Survival and Cellular Gene Expression

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