Fig. 10: Unified model for US9 function.

a MICA*008’s slow maturation process. Newly synthesized MICA*008 is recognized as misfolded by the ER quality control (ERQC) machinery, which retains it in the ER for repeated folding attempts and glycosylation trimming (1). Unknown factors (question mark) rescue MICA*008 from this cycle by slow delivery to the GPI-anchoring complex (2). GPI-anchored MICA*008 is recognized as properly folded, enabling its ER egress and expression on the cell surface (3). b US9 SP-dependent mode of function. The SP in the SP⁺ US9 form (highlighted in red) interferes with the GPI-anchoring promoting factors (red line) resulting in MICA*008 maturation arrest (1). MICA*008 is retained in the ER by the ERQC machinery and undergoes repeated folding attempts and progressive glycosylation trimming (2). Eventually, MICA*008 become terminally trimmed and lectins deliver it to the SEL1L-HRD1 ER-associated degradation (ERAD) complex (3), which sends MICA*008 to proteasomal degradation (4). c US9 SP-independent mode of function. SP⁺ US9 and SP⁻ US9 bind MICA*008 through their luminal Ig-like domain, and SEL1L through their TM domain (domains are highlighted in red) (1). This interaction leads to SEL1L-HRD1 mediated retrotranslocation and proteasomal degradation of MICA*008 (2), with no dependence on glycosylation trimming.