The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy.

The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

Signal transduction of FMS-like tyrosine kinase 3 (FLT3) is regulated by proteintyrosine phosphatases (PTPs). IntroductionAcute myeloid leukemia (AML) is the most frequent leukemia in adults with improving but still limited treatment possibilities, notably in elderly patients. 1,2 It arises by malignant transformation of myeloid progenitor cells. Among the contributing genetic lesions, mutations in the class III receptor tyrosine kinase (RTK) FMS-like tyrosine kinase 3 (FLT3) occur in approximately 30% of patients. 3 The prevalent type of FLT3 mutations are internal tandem duplications (ITD) of amino acid stretches in the juxtamembrane domain or in the tyrosine kinase domain, 4,5 which confer cytokineindependent proliferation and resistance to apoptosis, and causally contribute to AML in combination with additional genetic lesions. 1 Compared with the ligand-activated wild-type (WT) FLT3, FLT3 ITD mutants exhibit not only elevated but also altered signaling quality, with very pronounced activation of signal transducer and activator of transcription (STAT)5 as one characteristic feature. 6,7 FLT3 ITD also causes the production of high levels of reactive oxygen species (ROS). 8,9 Signal transduction of RTKs is regulated by protein-tyrosine phosphatases (PTPs). PTPs prevent ligand-independent RTK activation, and contribute to modulation and termination of ligand-induced signaling. 10 The activity of PTPs is regulated at several different levels. 11 One regulatory principle is the reversible oxidation of the PTP active-site cysteine, which leads to reversible inactivation. 12,13 Temporary inactivation of negatively regulating PTPs by this mechanism is believed to be important for efficient RTK signal propagation in the cell. 14 A major ROS causing cellular PTP oxidation is hydrogen peroxide (H 2 O 2 ), which can be generated by a dismutase reaction from superoxide anions, the reaction products of NADPH-oxidases. Activation of the NADPH oxidase isoform 1 (NOX1) occurs downstream of RTK activation, and involves activation and membrane translocation of the small guanosine triphosphate (GTP)ase Rac1. 15 ROS generation in the cell is counteracted by efficient ROS decomposing systems. 16 These include peroxiredoxins (Prx), which have a very low K m for H 2 O 2 and can eliminate it even at low concentrations. 17 Relatively little is known about PTPs regulating FLT3 signal transduction. We have previously shown that the nontransmembrane PTPs PTP1B and SHP-1 can potently dephosphorylate FLT3 on overexpression. Further, PTP1B appears important for suppressing signaling of newly synthesized FLT3. 7,18 SHP-2 acts as a positive regulator, because it is important for Erk activation and proliferation induced by ligand-activated WT FLT3. However, it is dispensable for FLT3 ITD-mediated transformation. 19 We previously performed a shRNA-based screen to identify PTPs regulating WT FLT3. The initial screen assessed the effects of shRNAs for 20 PTPs on FL-induced Erk1/2 activation in WT FLT3-expressing 32D cells. Among several potentia...

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