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CD4+ T cells orchestrate both humoral and cytotoxic immune responses. While it is known that CD4+ T cell proliferation relies on autophagy, direct identification of the autophagosomal cargo involved is still missing. Here, we created a transgenic mouse model, which, for the first time, enables us to directly map the proteinaceous content of autophagosomes in any primary cell by LC3 proximity labelling. IL-7Rα, a cytokine receptor mostly found in naïve and memory T cells, was reproducibly detected ...
Creators: Rainer Malik, Christian Behrends
Submitter: Rainer Malik
C9orf72 binds SMCR8 to from a robust complex that regulates small GTPases, lysosomal integrity and autophagy. In contrast to this functional understanding, we know far less about assembly and turnover of the C9orf72-SMCR8 complex. Loss of either subunit causes the concurrent ablation of the respective partner. However, the molecular mechanism underlying this interdependence remains elusive.
Creators: Rainer Malik, Christian Behrends
Submitter: Rainer Malik
Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare neurological disease caused by mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2) which possibly result in loss of the protein. Beside its potential role in autophagy, TECPR2 may serve as positive modulator of COPII-mediated ER export. However, the molecular consequences of TECPR2 deficiency for the secretory pathway remain unclear, in particular with regard to specific cargo proteins. By ...
Creators: Rainer Malik, Christian Behrends
Submitter: Rainer Malik
In the context of studying the role of the COP9 signalosome (CSN) in neuroinflammation and ischemic neuronal damage, we studied the effect of the cullin NEDDylation state-modifying drugs MLN4924 and CSN5i-3 in BV2 microglial cells, an immortalized murine cell line featuring many of the characteristics of primary microglia. Owing to its potent inhibitory effect on the NEDDylation cascade, MLN4924 exhibits a CSN5-like anti-inflammatory activity. Csn5i-3 is a small molecule inhibitor that specifically ...
Creators: Rainer Malik, Christian Behrends, Jürgen Bernhagen
Submitter: Rainer Malik
To determine how the mutant TBK1-E696K protein impacts autophagosomes, we performed autophagosome content profiling using protease protection coupled APEX2 proximity proteomics of autophagosomes of homozygous TBK1-E696K knockin and wiltype mouse embryonic fibroblasts (MEFs) transfected with a APEX2-LC3 as previously described in Zellner et al. 2021 Molecular Cell.
Creators: Rainer Malik, Christian Behrends
Submitter: Rainer Malik
While deleterious mutations are responsible for the vast majority of TBK1-linked ALS/FTD cases, the ALS/FTD causing missense mutation p.E696K leads to a selective loss of TBK1/optineurin binding. Knock-in of this specific missense mutation causes progressive autophagolysosomal dysfunction and an ALS/FTD-like phenotype in mice, while, as opposed to TBK1 deletion, RIPK/TNF-α-dependent necroptosis or overt inflammation are absent. Our results highlight the role of autophagolysosomal dysfunction as ...
Creators: Rainer Malik, Christian Behrends
Submitter: Rainer Malik