Biology subjects

Klimek, C.

Publications and source records attributed to Klimek, C..

3 recordsLinked to original sources

bioRxiv2024

The solute carrier superfamily interactome

Solute carrier (SLC) transporters form a protein superfamily that enables transmembrane transport of diverse substrates including nutrients, ions and drugs. There are about 450 different SLCs, residing in a variety of subcellular membranes. Loss-of-function of an unusually high proportion of SLC transporters is genetically associated with a plethora of human diseases, making SLCs a rapidly emerging but challenging drug target class. Knowledge of their protein environment may elucidate the molecular basis for their functional integration with metabolic and cellular pathways and help conceive pharmacological interventions based on modulating proteostatic regulation. We aimed at obtaining a global survey of the SLC protein interaction landscape and mapped the protein-protein interactions of 396 SLCs by interaction proteomics. We employed a functional assessment based on RNA interference of interactors in combination with measurement of protein stability and localization. As an example, we detail the role of a SLC16A6 phospho-degron, and the contributions of PDZ-domain proteins LIN7C and MPP1 to the trafficking of SLC43A2. Overall, our work offers a resource for SLC-protein interactions for the scientific community.

systems biology↗

bioRxiv2024

Metabolic mapping of the human solute carrier superfamily

Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked to cellular function and identity. Despite their key role, individual functions of the members of the SLC superfamily were not evaluated systematically. We determined the metabolic and transcriptional profiles upon SLC overexpression in knock-out or wild-type isogenic cell backgrounds. Targeted metabolomics provided a fingerprint of 189 intracellular metabolites, while transcriptomics offered insights into cellular programs modulated by SLC expression. Beyond the metabolic profiles of 102 SLCs directly related to their known substrates, we also identified putative substrates or metabolic pathway connections for 71 SLCs without previously annotated bona fide substrates, including SLC45A4 as a new polyamine transporter. By comparing the molecular profiles, we identified functionally related SLC groups, including some with distinct impacts on osmolyte balancing and glycosylation. The assessment of functionally related human genes presented here may serve as a blueprint for other systematic studies of human gene function and supports future investigations into the functional roles of SLCs.

systems biology↗

bioRxiv2018

The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy

Chaperone-assisted selective autophagy (CASA) initiated by the cochaperone Bcl2-associated athanogene 3 (BAG3) represents an important mechanism for the disposal of misfolded and damaged proteins in mammalian cells. Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin. This is essential for muscle maintenance in flies, fish, mice and men. Here, we identify the serine/threonine protein kinase 38 (STK38), which is part of the Hippo signaling network, as a novel interactor of BAG3. STK38 was previously shown to facilitate cytoskeleton assembly and to promote mitophagy as well as starvation and detachment induced autophagy. Significantly, our study reveals that STK38 exerts an inhibitory activity on BAG3-mediated autophagy. Inhibition relies on a disruption of the functional interplay of BAG3 with HSPB8 and SYNPO2 upon binding of STK38 to the cochaperone. Of note, STK38 attenuates CASA independently of its kinase activity, whereas previously established regulatory functions of STK38 involve target phosphorylation. The ability to exert different modes of regulation on central protein homeostasis (proteostasis) machineries apparently allows STK38 to coordinate the execution of diverse macroautophagy pathways and to balance cytoskeleton assembly and degradation.\n\nAbbreviationsBAG3, BCL2-associated athanogene; CASA, chaperone-assisted selective autophagy; CHIP, carboxy terminus of HSP70 interacting protein; EPS, electrical pulse stimulation; GST, glutathione-S-transferase; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; STK38, serine/threonine protein kinase 38.

cell biology↗