KICS2

KICS2 (C12orf66) is an integral subunit of the KICSTOR complex that couples nutrient availability to mTORC1 activity by recruiting the GATOR1 GTPase-activating complex to the lysosomal surface (PMID:28199306). Within KICSTOR, KICS2 assembles with the SZT2 scaffold at its C terminus alongside the ITFG2-KPTN heterodimer, while GATOR1 docks onto the SZT2 N-terminal domain via NPRL3; both SZT2 and KICS2 bind negatively charged lipids, an interaction required for lysosomal localization of the complex (PMID:41198956). By positioning GATOR1 at the lysosome, KICSTOR enables GATOR1 to act on Rag GTPases and thereby suppress mTORC1 during amino acid or glucose deprivation, so loss of the complex abolishes nutrient-deprivation-induced mTORC1 inhibition and mislocalizes the downstream transcription factor TFE3 (PMID:28199306, PMID:41198956). Consistent with this negative-regulatory role, CRISPR knockout of KICS2 sustains mTORC1 signaling and confers resistance to PI3Kα inhibition in PIK3CA-mutant breast cancer cells (PMID:33685991). The complex is itself regulated: FBXO2-mediated polyubiquitination of the KPTN subunit enhances KPTN's interaction with KICS2 while disrupting its association with ITFG2 and SZT2, impairing GATOR1 recruitment and promoting mTORC1 activation (PMID:41401028).

1. 2017 High

   Established that KICS2 is a bona fide subunit of a lysosomal complex (KICSTOR) whose function is to recruit GATOR1, defining how the nutrient-sensing machinery is physically organized at the lysosome.

   Evidence Co-IP, lysosomal fractionation, and CRISPR/siRNA loss-of-function with mTORC1 readouts in human cells and SZT2-knockout mice

   PMID:28199306

   Open questions at the time

   • Did not resolve the structural arrangement of subunits
   • Specific lipid determinants of lysosomal targeting not defined
2. 2021 Medium

   Demonstrated a cellular consequence of losing KICS2 — sustained mTORC1 signaling driving drug resistance — confirming its role as a negative mTORC1 regulator in a cancer context.

   Evidence Genome-wide CRISPR/Cas9 knockout screen with validation and pharmacological mTOR-inhibitor rescue in PIK3CA-mutant breast cancer cells

   PMID:33685991

   Open questions at the time

   • Single cell-type context
   • Does not address KICS2's molecular contribution within the complex versus other subunits
3. 2022 Medium

   Placed KICSTOR (including KICS2) downstream of an additional input by showing SAMTOR engages the GATOR1-KICSTOR complex to couple SAM levels to mTORC1.

   Evidence Apo and SAM-bound crystal structures of Drosophila SAMTOR with mutagenesis and mTORC1 signaling assays

   PMID:35776786

   Open questions at the time

   • KICS2 referenced as a complex member but not directly interrogated
   • Drosophila structure; human KICS2-SAMTOR contacts undefined
4. 2025 High

   Resolved the architecture of KICSTOR, showing how KICS2 binds the SZT2 C-terminus, how GATOR1 docks via NPRL3, and that lipid binding by SZT2 and KICS2 drives lysosomal localization.

   Evidence Cryo-EM structure with computational modeling, lipid-binding assays, and mutagenesis tied to mTORC1 and TFE3 localization readouts

   PMID:41198956

   Open questions at the time

   • KICS2's specific lipid-binding residues not separately dissected from SZT2
   • No structure of the full assembly bound to active GATOR1 substrates
5. 2025 Medium

   Identified a post-translational regulatory layer in which FBXO2 ubiquitination of KPTN remodels intra-complex interactions, including enhancing the KPTN-KICS2 association while weakening GATOR1 recruitment.

   Evidence Co-IP, linkage-specific ubiquitination assays, lysine-site mutagenesis, and loss-of-function with mTORC1 readouts

   PMID:41401028

   Open questions at the time

   • Functional meaning of the strengthened KPTN-KICS2 interaction not fully resolved
   • Single lab; physiological triggers of FBXO2 activity undefined

• The distinct molecular contribution of KICS2 relative to the other KICSTOR subunits — and whether it carries any catalytic or signaling function beyond lipid-anchored scaffolding — remains unresolved.
• No KICS2-specific separation-of-function studies
• No KICS2 disease association established in the corpus