Deubiquitinating enzymes (DUBs) remove ubiquitin (Ub) from Ub-conjugated 
substrates to regulate the functional outcome of ubiquitylation. Here we report 
the discovery of a new family of DUBs, which we have named MINDY (motif 
interacting with Ub-containing novel DUB family). Found in all eukaryotes, 
MINDY-family DUBs are highly selective at cleaving K48-linked polyUb, a signal 
that targets proteins for degradation. We identify the catalytic activity to be 
encoded within a previously unannotated domain, the crystal structure of which 
reveals a distinct protein fold with no homology to any of the known DUBs. The 
crystal structure of MINDY-1 (also known as FAM63A) in complex with 
propargylated Ub reveals conformational changes that realign the active site for 
catalysis. MINDY-1 prefers cleaving long polyUb chains and works by trimming 
chains from the distal end. Collectively, our results reveal a new family of 
DUBs that may have specialized roles in regulating proteostasis.