Proteomics

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A comprehensive set of ER PDI family members supports the biogenesis of pro-inflammatory interleukin 12 family cytokines


ABSTRACT: Cytokines of the interleukin 12 (IL-12) family are assembled combinatorially from shared alpha and beta subunits. A common theme is that human IL-12 family alpha subunits remain incompletely structured in isolation until they pair with a designate beta subunit. Accordingly, chaperones need to support and control specific assembly processes. Here, we site-specifically introduce photo-crosslinking amino acids into the IL-12 and IL-23 alpha subunits (IL-12alpha and IL-23alpha). This allows to stabilize transient chaperone:client complexes for mass spectrometry and reveals a large set of ER chaperones to interact with IL-12alpha and IL-23alpha. Among those, we focus on protein disulfide isomerase (PDI) family members and reveal IL-12 family subunits to be clients of several ill-characterized PDIs. We find that different PDIs show selectivity for different cysteines in IL-12alpha and IL-23alpha. Despite this, PDI binding generally stabilizes unassembled IL-12alpha and IL-23alpha against degradation. In contrast, alpha:beta assembly appears robust and only multiple simultaneous PDI depletions reduce IL-12 secretion. Our comprehensive analysis of the IL-12/IL-23 chaperone machinery reveals a hitherto uncharacterized role for several PDIs in this process. This extends our understanding of how cells accomplish the task of specific protein assembly reactions for signaling processes. Furthermore, our findings show that cytokine secretion can be modulated by targeting specific ER chaperones.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Nina Bach  

LAB HEAD: Matthias J. Feige

PROVIDER: PXD036463 | Pride | 2022-11-28

REPOSITORIES: Pride

Dataset's files

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1_1_5873.d.zip Other
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1_2_5875.d.zip Other
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Publications

A comprehensive set of ER protein disulfide isomerase family members supports the biogenesis of proinflammatory interleukin 12 family cytokines.

Mideksa Yonatan G YG   Aschenbrenner Isabel I   Fux Anja A   Kaylani Dinah D   Weiß Caroline A M CAM   Nguyen Tuan-Anh TA   Bach Nina C NC   Lang Kathrin K   Sieber Stephan A SA   Feige Matthias J MJ  

The Journal of biological chemistry 20221104 12


Cytokines of the interleukin 12 (IL-12) family are assembled combinatorially from shared α and β subunits. A common theme is that human IL-12 family α subunits remain incompletely structured in isolation until they pair with a designate β subunit. Accordingly, chaperones need to support and control specific assembly processes. It remains incompletely understood, which chaperones are involved in IL-12 family biogenesis. Here, we site-specifically introduce photocrosslinking amino acids into the I  ...[more]

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