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MARCH8 (c-MIR) is a novel E3 ubiquitin ligase designated as the modulator of immune recognition (MIR) family, whose catalytic domain is a variant RING domain (RING-CH domain). MARCH8 was found as a functional and structural homolog of KSHV MIR1 and MIR2. MARCH8 targets B7-2 to lysosomal degradation and down-regulates the B7-2 surface expression through ubiquitination of its cytoplasmic tail. Furthermore, MARCH8 has been shown to down-regulate the expression of transferrin receptor and Fas, an important molecule for the induction of apoptosis. MARCH8 is the first example of an E3 ubiquitin ligase that is capable of inhibiting MHC II expression. Recent findings suggest that MARCH8 may regulate immune responses by promoting ubiquitination of MHC-II and CD86, leading to their subsequent endocytosis and lysosomal degradation.