Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase

Pattern recognition receptors (PRRs) play a key role in plant and animal innate immunity. PRR binding of their cognate ligand triggers a signaling network and activates an immune response. Activation of PRR signaling must be controlled prior to ligand binding to prevent spurious signaling and immune activation. Flagellin perception in Arabidopsis through FLAGELLIN‐SENSITIVE 2 (FLS2) induces the activation of mitogen‐activated protein kinases (MAPKs) and immunity. However, the precise molecular mechanism that connects activated FLS2 to downstream MAPK cascades remains unknown. Here, we report the identification of a differentially phosphorylated MAP kinase kinase kinase that also interacts with FLS2. Using targeted proteomics and functional analysis, we show that MKKK7 negatively regulates flagellin‐triggered signaling and basal immunity and this requires phosphorylation of MKKK7 on specific serine residues. MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of FLS2, suggesting that MKKK7‐mediated attenuation of FLS2 signaling occurs through direct modulation of the FLS2 complex.     

Loss of CLPP alleviates mitochondrial cardiomyopathy without affecting the mammalian UPRmt

The mitochondrial matrix protease CLPP plays a central role in the activation of the mitochondrial unfolded protein response (UPR^mt) in Caenorhabditis elegans. Far less is known about mammalian UPR^mt signaling, although similar roles were assumed for central players, including CLPP. To better understand the mammalian UPR^mt signaling, we deleted CLPP in hearts of DARS2‐deficient animals that show robust induction of UPR^mt due to strong dysregulation of mitochondrial translation. Remarkably, our results clearly show that mammalian CLPP is neither required for, nor it regulates the UPR^mt in mammals. Surprisingly, we demonstrate that a strong mitochondrial cardiomyopathy and diminished respiration due to DARS2 deficiency can be alleviated by the loss of CLPP, leading to an increased de novo synthesis of individual OXPHOS subunits. These results question our current understanding of the UPR^mt signaling in mammals, while introducing CLPP as a possible novel target for therapeutic intervention in mitochondrial diseases.     

Understanding the burnout experience: recent research and its implications for psychiatry

The experience of burnout has been the focus of much research during the past few decades. Measures have been developed, as have various theoretical models, and research studies from many countries have contributed to a better understanding of the causes and consequences of this occupationally‐specific dysphoria. The majority of this work has focused on human service occupations, and particularly health care. Research on the burnout experience for psychiatrists mirrors much of the broader literature, in terms of both sources and outcomes of burnout. But it has also identified some of the unique stressors that mental health professionals face when they are dealing with especially difficult or violent clients. Current issues of particular relevance for psychiatry include the links between burnout and mental illness, the attempts to redefine burnout as simply exhaustion, and the relative dearth of evaluative research on potential interventions to treat and/or prevent burnout. Given that the treatment goal for burnout is usually to enable people to return to their job, and to be successful in their work, psychiatry could make an important contribution by identifying the treatment strategies that would be most effective in achieving that goal.