STK11IP

STK11IP (LKB1IP) is a lysosome-associated regulator of autophagy that couples mTORC1 signalling to control of lysosomal acidification (PMID:35365663). On the lysosome surface, mTORC1 phosphorylates STK11IP at Ser404, and in this phosphorylated state STK11IP binds V-ATPase and suppresses its activity, thereby limiting lysosomal acidification and restraining autophagy flux; loss of STK11IP or dephosphorylation of Ser404 de-represses autophagy (PMID:35365663). This inhibitory STK11IP–mTOR–V-ATPase assembly is antagonised by VASN, which interacts with lysosomal mTOR and STK11IP and disrupts STK11IP binding to mTOR and V-ATPase, relieving the suppression of acidification (PMID:41630427). Beyond the lysosome, STK11IP directly inhibits PTEN phosphatase activity to activate Akt signalling and drives pathological cardiac hypertrophy, as STK11IP knockout protects mice from ISO- and TAC-induced hypertrophy and fibrosis (PMID:33486894).

1. 2021 Medium

   Established a non-lysosomal, pro-pathological role for STK11IP by showing it directly inhibits PTEN to drive Akt-dependent cardiac hypertrophy.

   Evidence LKB1IP knockout mice challenged with ISO or TAC, plus cardiomyocyte gain/loss-of-function and PTEN phosphatase activity assays

   PMID:33486894

   Open questions at the time

   • Single lab; mechanism of direct PTEN inhibition not structurally defined
   • Relationship between this PTEN-targeting role and the lysosomal V-ATPase function is unaddressed
   • No structural basis for STK11IP–PTEN interaction
2. 2022 High

   Defined STK11IP as a direct mTORC1 substrate (Ser404) that gates autophagy by binding and suppressing V-ATPase to limit lysosomal acidification.

   Evidence Lysosomal phosphoproteomics cross-referenced with mTORC1 targets, STK11IP knockout mice, autophagy flux assays, co-IP with V-ATPase, and Ser404 phosphomutants

   PMID:35365663

   Open questions at the time

   • Which V-ATPase subunit STK11IP contacts is not resolved
   • Phosphatase responsible for Ser404 dephosphorylation not identified
   • Stoichiometry and structure of the STK11IP–V-ATPase interaction unknown
3. 2026 Medium

   Placed STK11IP within a regulatable module by identifying VASN as an antagonist that disrupts STK11IP binding to mTOR and V-ATPase to relieve acidification suppression.

   Evidence Lysosomal co-IP with DSP crosslinking, co-localization imaging, binding-competition assays, and lysosomal acidification readouts

   PMID:41630427

   Open questions at the time

   • Single lab; reciprocal validation of the VASN displacement mechanism in vivo not shown
   • How VASN access to lysosomal STK11IP is controlled is unknown
   • Whether VASN antagonism intersects the PTEN/cardiac axis is untested

• Whether the lysosomal V-ATPase regulatory role and the PTEN-inhibitory cardiac role reflect one integrated mechanism or distinct activities remains unresolved.
• No study links STK11IP's autophagy/V-ATPase function to its PTEN/Akt function
• Domain architecture mediating the distinct interactions is uncharacterized
• Tissue-specific determinants of which role dominates are unknown