TGFB-inducible VASN (vasorin) promotes lysosomal acidification

The lysosome is not only a degradative organelle but also an essential platform for signal transduction, such as with MTOR signaling. The reciprocal regulation between the lysosome and MTOR is central to macroautophagy/autophagy and metabolism. MTOR-mediated suppression of lysosomal acidification is important for lysosomal activity, autophagic flux, and cell survival. VASN is a transmembrane glycoprotein whose function is not fully understood. In the present study, we report that VASN is a TGFB-inducible protein and plays a crucial role in positively regulating lysosomal acidification. As a potential mechanism, we demonstrated that VASN localizes to the lysosome, interacts with lysosomal MTOR and STK11IP, and disrupts the binding of STK11IP to MTOR and the V-ATPase, which was recently reported to suppress lysosomal acidification. We found that VASN's function in modulating lysosomal activity is essential for optimal mitophagy induced by TGFB and terminal erythroid differentiation and is critical for the progression of mutant KRAS-driven lung cancer. Overall, our study identified VASN as a novel TGFB-inducible regulator of lysosomal function.<b>Abbreviations</b>: ATG5, autophagy related 5; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CLEM, correlative-light electron microscopy; DSP, dithiobis(succinimidyl propionate); EGFP, enhanced green fluorescent protein; EYFP, enhanced yellow fluorescent protein; FIB-SEM, focused ion beam-scanning electron microscopy; LAMP1, lysosomal-associated membrane protein 1; LysoIP, lysosomal immunoprecipitation; MAP1LC3B, microtubule-associated protein 1 light chain 3 beta; MTOR, mechanistic target of rapamycin kinase; RBCs, red blood cells; SMAD, SMAD family member; STK11IP, serine/threonine kinase 11 interacting protein; TEM, transmission electron microscopy; TGFB, transforming growth factor beta; TGOLN2/TGN38, trans-golgi network protein 2; TMEM192, transmembrane protein 192; V-ATPase, vacuolar-type H⁺-translocating ATPase.