Tissue-resident memory T (TRM) cells exist throughout the body, where they are poised to mediate local immune responses. Although studies have defined a common mechanism of residency independent of location, there is likely to be a level of specialization that adapts TRM cells to their given tissue of lodgment. It has been shown that TRM cells in the skin rely on the uptake of exogenous fatty acids for their survival and up-regulate fatty acid–binding protein 4 (FABP4) and FABP5 as part of their transcriptional program. However, FABPs exist as a larger family of isoforms, with different members selected in a tissue-specific fashion that is optimized for local fatty acid availability. Here, we show that although TRM cells in a range of tissue widely express FABPs, they are not restricted to FABP4 and FABP5. Instead, TRM cells show varying patterns of isoform usage that are determined by tissue-derived factors. These patterns are malleable because TRM cells relocated to different organs modify their FABP expression in line with their new location. As a consequence, these results argue for tissue-specific overlays to the TRM cell residency program, including FABP expression that is tailored to the particular tissue of TRM cell lodgment.
The human GID (hGID) complex is an evolutionary conserved E3 ubiquitin ligase regulating diverse biological processes including glucose metabolism and cell cycle progression. However, the biochemical function and substrate recognition of the multi-subunit complex remains poorly understood. While the yeast GID complex recognizes Pro/N-end rule substrates via yeast Gid4, the human GID complex requires a WDR26/Gid7-dependent module to trigger proteasomal degradation of mammalian HBP1. Here, using biochemical assays, crosslinking-mass spectrometry and cryo-electron microscopy, we show that hGID unexpectedly engages two distinct modules for substrate recruitment, dependent on either WDR26 or GID4. WDR26 together with RanBP9 cooperate to ubiquitinate HBP1 in vitro, while GID4 is dispensable for this reaction. In contrast, GID4 functions as an adaptor for the substrate ZMYND19, which surprisingly lacks a Pro/N-end rule degron. GID4 substrate binding and ligase activity is regulated by ARMC8 alpha, while the shorter ARMC8 beta; isoform assembles into a stable hGID complex that is unable to recruit GID4. Cryo-EM reconstructions of these hGID complexes reveal the localization of WDR26 within a ring-like, tetrameric architecture and suggest that GID4 and WDR26/Gid7 utilize different, non-overlapping binding sites. Together, these data advance our mechanistic understanding of how the hGID complex recruits cognate substrates and provide insights into the regulation of its ligase activity.
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