A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation

IκB kinase 2 (IKK2) is well known for its pivotal role as a mediator of the canonical NF-κB pathway, which has important functions in inflammation and immunity, but also in cancer. Here we identify a novel and critical function of IKK2 and its co-factor NEMO in the activation of oncogenic c-Jun N-terminal kinase (JNK) signaling, induced by the latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV). Independent of its kinase activity, the TGFβ-activated kinase 1 (TAK1) mediates LMP1 signaling complex formation, NEMO ubiquitination and subsequent IKK2 activation. The tumor progression locus 2 (TPL2) kinase is induced by LMP1 via IKK2 and transmits JNK activation signals downstream of IKK2. The IKK2-TPL2-JNK axis is specific for LMP1 and differs from TNFα, Interleukin-1 and CD40 signaling. This pathway mediates essential LMP1 survival signals in EBV-transformed human B cells and post-transplant lymphoma, and thus qualifies as a target for treatment of EBV-induced cancer

Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) drives viral B cell transformation and oncogenesis. LMP1’s transforming activity depends on its C-terminal activation region 2 (CTAR2), which induces NF-κB and JNK by engaging TNF receptor-associated factor 6 (TRAF6). The mechanism of TRAF6 recruitment to LMP1 and its role in LMP1 signalling remains elusive. Here we demonstrate that TRAF6 interacts directly with a viral TRAF6 binding motif within CTAR2. Functional and NMR studies supported by molecular modeling provide insight into the architecture of the LMP1-TRAF6 complex, which differs from that of CD40-TRAF6. The direct recruitment of TRAF6 to LMP1 is essential for NF-κB activation by CTAR2 and the survival of LMP1-driven lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with the survival of EBV-transformed B cells. In this work, we identify LMP1-TRAF6 as a critical virus-host interface and validate this interaction as a potential therapeutic target in EBV-associated cancer.Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.Deutsche Forschungsgemeinschaft (German Research Foundation)https://doi.org/10.13039/501100001659Deutsches Zentrum für Infektionsforschung (German Center for Infection Research)https://doi.org/10.13039/100009139Life Science Foundatio

Real-time imaging using a 4.3-THz quantum cascade laser and a 320×240 microbolometer focal-plane array

Abstract: We report on the development of a compact, easy-to-use terahertz radiation source, which combines a quantum-cascade laser (QCL) operating at 3.1 THz with a compact, low-input-power Stirling cooler. The QCL, which is based on a two-miniband design, has been developed for high output and low electrical pump power. The amount of generated heat complies with the nominal cooling capacity of the Stirling cooler of 7 W at 65 K with 240 W of electrical input power. Special care has been taken to achieve a good thermal coupling between the QCL and the cold finger of the cooler. The whole system weighs less than 15 kg including the cooler and power supplies. The maximum output power is 8 mW at 3.1 THz. With an appropriate optical beam shaping, the emission profile of the laser is fundamental Gaussian. The applicability of the system is demonstrated by imaging and molecular-spectroscopy experiments. Hübers, "Sub-megahertz frequency stabilization of a terahertz quantum cascade laser to a molecular absorption line," Appl. Phys. Lett. 96(7), 071112 (2010). ©2010 Optical Society of Americ

Broadband molecular spectroscopy with a multi-mode THz quantum cascade laser (QCL)

High-resolution molecular spectroscopy is a powerful tool for investigations of the structure and energy levels of molecules and atoms. In addition to the scientific interest, terahertz (THz) spectroscopy is also of interest for the detection and identification of gases in safety and security applications. While for frequencies below 2 THz many different methods have been developed, spectroscopy above 2 THz is hampered by the lack of frequency-tunable, continuous-wave, powerful, and narrow-linewidth radiation sources. For this frequency range, THz quantum-cascade lasers (QCLs) are promising radiation sources. We report on a THz absorption spectrometer, which combines a grating monochromator, a QCL, and a microbolometer camera. The QCL used in these experiments contains a single-plasmon waveguide and a Fabry-Pérot cavity with both facets uncoated. It is optimized for low electrical pumping powers an emits several modes centered around 3.4 THz. The laser is mounted in a compact air-cooled cryocooler (model K535 from Ricor). The emitted beam is focused with a TPX lens and guided through a 27 cm long absorption cell onto the monochromator, which spectrally resolves the laser modes. The modes are imaged onto the microbolometer camera. The absorption spectrum of methanol around 3.4 THz is measured by detecting simultaneously the signal of each of the laser modes as a function of the laser driving current. By this means, frequency multiplexing is achieved

Molecular spectroscopy with a multimode THz quantum-cascade laser

A terahertz absorption spectrometer for highresolution molecular spectroscopy is realized. The spectrometer is based on a multimode quantum-cascade laser. The design and performance of the spectrometer are presented. Three aspects are discussed: sensitivity, frequency calibration, and frequency multiplexing

Molecular spectroscopy with a multimode THz quantum-cascade laser

High-resolution molecular spectroscopy is a powerful tool for investigations of the structure and energy levels of molecules and atoms. In addition to scientific utilization, terahertz (THz) spectroscopy is of interest for detection and identification of gases in safety and security applications. While for frequencies below 2 THz many different methods have been developed, spectroscopy above 2 THz is hampered by the lack of frequency-tunable, continuous-wave, powerful, and narrow-linewidth radiation sources. For this frequency range, THz quantum-cascade lasers (QCLs) are promising radiation sources. We report on a THz absorption spectrometer, which combines a grating monochromator, a QCL, and a microbolometer camera. The QCL used for these experiments is based on a single-plasmon waveguide and a Fabry-Pérot cavity with both facets uncoated and is optimized for a low electrical pump power. It operates on several modes centered around 3.4 THz. The laser is mounted in a compact air-cooled cryocooler (model K535 from Ricor). The emitted beam is focused with a TPX lens and guided through a 27 cm long absorption cell onto the monochromator, which spectrally resolves the laser modes. The modes are imaged onto the microbolometer camera. The absorption spectrum of methanol around 3.4 THz is measured by detecting simultaneously the signal of each of the laser modes as a function of the laser driving current

THz Quantum-Cascade Laser as Local Oscillator for SOFIA

We report on the development of a compact local oscillator (LO) for operation on board of SOFIA, namely for GREAT, the German Receiver for Astronomy at Terahertz Frequencies. The LO combines a quantum-cascade laser (QCL) with a compact, low-input-power Stirling cooler. The output power is sufficient for pumping a hot-electron bolometer mixer. Frequency stabilization is achieved by locking to a molecular absorption line. Detectors operating at room temperature can be used for the stabilization as well. High-resolution molecular spectroscopic experiments demonstrate the usability as LO for SOFIA

A compact, continuous-wave radiation source for local oscillator applications based on a THz quantum-cascade laser

Heterodyne spectroscopy of molecular rotational lines and atomic fine-structure lines is a powerful tool in astronomy and planetary research. It allows for studying the chemical composition, the evolution, and the dynamical behaviour of many astronomical objects. As a consequence, current and future airborne as well as spaceborne observatories such as SOFIA, Herschel or Millimetron are equipped with heterodyne spectrometers. A major challenge for heterodyne receivers operating above approximately 2 THz is the local oscillator, which should be a compact source requiring little electrical input power. THz quantum-cascade lasers (QCLs) have the potential to comply with these requirements. However, until now, THz QCLs operate at rather low temperatures so that cooling by liquid helium or using large cryo-coolers becomes necessary. While these cooling approaches might be acceptable for laboratory experiments, they either result in too many restrictions on airborne or spaceborne heterodyne receivers or are completely unacceptable. We report on the development of a compact, easy-to-use source, which combines a QCL operating at 3.1 THz with a compact, low-input-power Stirling cooler. The QCL, which is based on a two-miniband design, has been developed for high output powers and low electrical pump powers [1]. Efficient carrier injection is achieved by resonant longitudinal-optical phonon scattering. At the same time, the operating voltage can be kept below 6 V. The amount of generated heat complies with the cooling capacity of the Stirling cooler of 7 W at 65 K with 240 W of electrical input power. Special care has been taken to achieve a good thermal coupling between the QCL and the cold finger of the cryostat. The whole system weighs less than 15 kg including cooler, power supplies etc. The output power is well above 1 mW at 3.1 THz. With an appropriate optical beam shaping, the emission profile of the laser becomes a fundamental Gaussian one. In addition to the performance of the QCL in the Stirling cooler, we will present results of the application of this source to highresolution molecular spectroscopy