The transcription factor HIF1 is mostly regulated by the oxygen-dependent 
proteasomal degradation of the labile subunit HIF1A. Recent data showed 
degradation of HIF1A in the lysosome through chaperone-mediated autophagy (CMA). 
However the molecular mechanism involved has not been elucidated. This study 
shows that the KFERQ-like motif, that has been identified in all CMA substrates, 
is required to mediate the interaction between HIF1A and the chaperone HSPA8. 
Moreover, mutations in the KFERQ-like motif of HIF1A preclude the interaction 
with the CMA receptor LAMP2A, thus inhibiting its lysosomal degradation. 
Importantly, we show for the first time that the ubiquitin ligase STUB1 is 
required for degradation of HIF1A in the lysosome by CMA. Indeed, mutations in 
STUB1 that inhibit either the ubiquitin ligase activity or its ability to bind 
to HSPA8, both prevent degradation of HIF1A by CMA. Moreover, we show that HIF1A 
binds to and is translocated into intact lysosomes isolated from rat livers. 
This new pathway for degradation of HIF1A does not depend on the presence of 
oxygen and is activated in response to nutrient deprivation such that the levels 
of HIF1A bound to CMA positive lysosomes significantly increase in starved 
animal livers and the binding of HIF1A to LAMP2A increases in response to serum 
deprivation. Moreover, excessive degradation of HIF1A by CMA compromises cells' 
ability to respond to and survive under hypoxia, suggesting that this pathway 
might be of pathophysiological importance in conditions that combine hypoxia 
with starvation.